Gastroenterology Insights — Clinical Updates, Guides & Resources — Page 2

5 min readAug 10, 202626reads

Cholesterol Metabolism in Pancreatic Cancer 2026: Why FOLFIRINOX Resistance May Start With a Lipid Pathway, Not a Mutation

A 61-year-old man with borderline-resectable PDAC completes six cycles of neoadjuvant FOLFIRINOX. Restaging imaging shows a tumor that has barely moved, and repeat biopsy shows a spindled, mesenchymal-appearing population that wasn't dominant on the original specimen. Genomic testing is unremarkable - no new KRAS variant, no acquired resistance mutation. The tumor didn't mutate its way out of chemotherapy. It may have metabolically reprogrammed its way out instead, and new NCI-funded work out of the University of Oklahoma is pointing at cholesterol handling as the mechanism. The core clinical problem PDAC's resistance to FOLFIRINOX and gemcitabine-based regimens is well documented, but most of the mechanistic literature centers on stromal density, hypoxia, and drug efflux transporters - targets that have been difficult to translate into anything actionable at the bedside. What's newer, and what this research direction adds, is a specific molecular route by which pancreatic cancer cells appear to reprogram cholesterol metabolism under therapeutic stress, and in doing so acquire both drug tolerance and a more invasive, epithelial-to-mesenchymal transition phenotype. If tumor ZC3H15 expression tracks with treatment failure the way early data suggest, cholesterol metabolism moves from a peripheral finding to a plausible therapeutic target - one that happens to already have an FDA-approved, inexpensive drug sitting on the shelf. The ZC3H15–KDM3A–cholesterol axis The University of Oklahoma team, led by investigator Sunil Kumar Shukla and supported by a five-year, $2 million NCI R01 grant, identified ZC3H15 as an RNA-binding protein that stabilizes transcripts encoding KDM3A, a histone demethylase. By protecting the RNA instructions for producing KDM3A, ZC3H15 appears to change how pancreatic cancer cells use cholesterol. In preliminary studies, tumors with high ZC3H15 expression were associated with chemotherapy resistance and worse survival - a correlation strong enough to justify the funded mechanistic follow-up. The downstream consequence is where this gets clinically interesting. The cholesterol-related changes triggered by this axis appear to drive epithelial-to-mesenchymal transition, making cancer cells more mobile and adaptable rather than simply making them proliferate faster. That distinction matters: a tumor that survives chemotherapy by becoming more resistant to apoptosis and more capable of dissemination behaves differently on imaging and in the clinic than one that is simply growing through treatment. It helps explain a pattern many gastroenterologists and GI oncologists have seen anecdotally - post-FOLFIRINOX tumors that look biologically tougher, not just bigger. Case in point A 58-year-old woman with metastatic PDAC to the liver responds well to first-line FOLFIRINOX for four months - CA 19-9 drops by more than 80%, and hepatic lesions shrink on CT. At month five, CA 19-9 begins climbing again despite continued therapy, and a new liver lesion appears outside the previously treated field, with morphology suggesting a more infiltrative growth pattern than the original disease. The oncology team faces the familiar dilemma of whether this represents true progression warranting a regimen switch or a transient flare. What the ZC3H15–KDM3A framework offers, if validated, is a biological explanation for why "resistant" PDAC so often reappears as more aggressive rather than merely unresponsive - a metabolic shift toward EMT rather than a static drug-efflux problem. It reframes the question from "which second-line regimen" to "is there a metabolic vulnerability worth targeting alongside cytotoxic therapy." Rosuvastatin as a chemosensitizer - the translational hook The most immediately actionable part of this research program is the plan to test whether rosuvastatin, a widely prescribed statin, can restore chemosensitivity when combined with FOLFIRINOX. The investigators will evaluate whether rosuvastatin, despite being prescribed primarily to lower cholesterol, can also disrupt the cholesterol-related changes that help pancreatic cancer resist chemotherapy, using patient-derived tumor models and genetically engineered mouse models over the five-year grant period. The appeal here is practical rather than purely scientific. Statins are cheap, familiar to every clinician, have a well-characterized safety profile, and are already used in a large proportion of PDAC patients for cardiovascular indications - meaning any positive signal could move toward clinical testing faster than a novel compound would. That said, "well-tolerated and already prescribed" is not the same as "proven to chemosensitize PDAC in humans." This work is currently confined to laboratory models grown from patient tumors and specially bred mice; there is no clinical trial data yet, and extrapolating a benefit to patients on statins for cardiovascular reasons would be premature. A frequently overlooked point Clinicians tend to treat incidental statin use in PDAC patients as background noise - a comorbidity medication unrelated to the cancer itself. This research suggests that assumption deserves reconsideration, not because there's yet evidence to change prescribing, but because the biological plausibility of a cholesterol-lowering drug interacting with tumor behavior is no longer speculative. It's also worth remembering that EMT-associated resistance doesn't show up on genomic panels - a patient with a "clean" resistance workup and no actionable mutation may still be undergoing a metabolic transition that current testing simply isn't built to detect. Bottom line for clinical practice Genomically "unremarkable" chemoresistant PDAC may still be undergoing metabolic reprogramming - absence of a resistance mutation doesn't rule out a biological escape route. The ZC3H15–KDM3A–cholesterol axis is preclinical and correlative at this stage; do not adjust statin prescribing or treatment selection based on this pathway yet. Track this research program (NCI award R01CA316828-01) for early signals on rosuvastatin plus FOLFIRINOX combination data before it reaches clinical trial stage. Consider that post-treatment tumors with a more invasive phenotype on imaging or biopsy may reflect EMT-driven adaptation rather than simple undertreatment. Cholesterol metabolism as a druggable vulnerability in PDAC is still five years of laboratory work away from bedside relevance, but it's the kind of mechanism worth tracking now - because the proposed intervention is a drug already in your patients' medicine cabinets. When you're working through a resistant PDAC case and the genomics come back clean, GastroAGI can help you reason through the less obvious explanations, including emerging metabolic and epigenetic resistance pathways like this one.

GastroAGI TeamRead more

11 min readAug 8, 20260reads

After ESD, the Pathology Report Becomes the Risk Map: International Standards for Early GI Cancer

The Lesion Is Out. The Oncologic Decision Is Not Over. There is a satisfying moment at the end of a technically successful endoscopic submucosal dissection. The lesion has been removed en bloc. Hemostasis is secure. The specimen is retrieved intact. From the endoscopist’s perspective, much of the difficult work appears to be finished. For the patient, however, the more important question is only beginning: Was the resection actually curative? That answer does not come from the endoscopic photograph. It comes from the pathology report. A few micrometres of submucosal invasion, the presence or absence of lymphovascular invasion, a positive deep margin, tumour budding, histological subtype, or uncertainty created by poor specimen orientation can alter what happens next. Surveillance may be enough. Another endoscopic intervention may be appropriate. Staging or surgery may be required. The international consensus article “Risk-based pathology reporting after endoscopic submucosal dissection for early gastrointestinal cancer: international consensus standards,” published online in Gut on 10 July 2026, attempts to make those decisions more reproducible. The paper used a modified Delphi process to establish practical standards for pathological assessment and reporting of invasive carcinoma in ESD specimens. That distinction matters from the outset. This is not a clinical trial. It is not a prospective outcomes cohort. And it does not prove that every reporting variable independently improves survival. Its purpose is more immediate and operational: to reduce variation in how ESD specimens are assessed and reported so that the multidisciplinary team is working from the same pathological language. An International Attempt to Standardise a Difficult Interface The consensus panel included 42 experts from 15 countries : 28 gastrointestinal pathologists 14 therapeutic endoscopists They completed five iterative Delphi survey rounds between January and September 2025. Consensus was predefined as at least 80% of responding panelists scoring a statement 4 or higher on a 5-point Likert scale. Across those rounds, 56 recommendations reached consensus in seven broad domains covering: submucosal invasion depth submucosal invasion breadth margin evaluation staining methods measurement protocols lymph-node metastasis risk and tumour budding clinical evaluation The authors’ conclusion is deliberately practical. These standards are intended to be implementable now, including through synoptic pathology reporting. For clinicians, that may ultimately be more useful than another elegant classification system that never quite escapes the supplementary appendix. Why Gastroenterologists Should Care About Pathology Standardisation ESD is often discussed in technical terms. En bloc resection. R0 resection. Dissection speed. Bleeding. Perforation. Procedure time. All important. But technical success and oncologic adequacy are not identical. Once invasive carcinoma is identified, the pathology specimen becomes the basis for estimating the risk of residual disease and lymph-node metastasis. That assessment depends on several features: depth of submucosal invasion resection margins lymphovascular invasion tumour budding differentiation histological subtype perineural invasion If those variables are measured or reported inconsistently, the multidisciplinary discussion starts with uncertainty. And no amount of endoscopic elegance can completely rescue a poorly handled specimen. This becomes particularly relevant as ESD expands beyond high-volume centres in East Asia into Western practice and more diverse institutional settings. A beautifully performed ESD followed by inadequate pinning, poor orientation, incomplete embedding, or vague pathology reporting can turn a potentially precise oncologic decision into an unnecessarily difficult one. The message is straightforward: Specimen handling and pathology reporting are part of the cancer procedure. They are not clerical events that happen afterwards. Submucosal Invasion: Measure What You Can Actually Defend One of the clearest recommendations concerns submucosal invasion depth. The consensus advises using Sm1–Sm3 subclassification only when muscularis propria is present. When it is not, invasion depth should be reported in micrometres, rounded to the nearest 100 μm. This is a sensible attempt to avoid false precision. Many ESD specimens do not contain the full thickness of the submucosa or muscularis propria. In that setting, assigning Sm1, Sm2, or Sm3 may suggest anatomical certainty that the specimen simply does not provide. A direct linear measurement is often more reproducible. The consensus recommends measuring invasion from the base or deepest fibre of the muscularis mucosae to the deepest point of tumour invasion. Of course, pathology rarely behaves as neatly as the diagram in a textbook. The muscularis mucosae may be duplicated, disrupted, absent, distorted, or incorporated into the lesion. When that occurs, the panel allows alternative approaches, including reconstruction of a virtual baseline from adjacent intact mucosa or measurement from the tumour surface. The potential for overestimating invasion should be recognised when these alternatives are used. That degree of transparency is important. A measurement accompanied by an explanation of its limitations is often more clinically valuable than an apparently exact number built on uncertain anatomy. Depth Matters—but It Should Not Stand Alone For years, depth of submucosal invasion has attracted considerable attention because of its relationship with lymph-node metastasis risk. The consensus does not dismiss that importance. But it places depth within a broader histological context. Risk assessment should also incorporate features such as: lymphovascular invasion tumour budding differentiation margin status histological subtype This is one of the more clinically mature aspects of the paper. We are often drawn to single thresholds because they make decisions appear cleaner. Biology is rarely so cooperative. A patient with relatively limited invasion but clear lymphovascular invasion does not carry the same risk as a patient with the same depth measurement and no adverse histological features. The report therefore needs to provide the ingredients for a composite oncologic assessment, rather than inviting the team to anchor on one number. Measuring the Breadth of Invasion: Useful Data, Uncertain Prognosis The panel also recommends reporting submucosal invasion breadth in millimetres. Breadth is defined as the greatest lateral extent of invasive submucosal carcinoma within the specimen. This is a more forward-looking recommendation. The evidence supporting breadth as an independent prognostic factor remains limited and inconsistent. The consensus does not claim otherwise. That restraint is important. Clinicians should not begin using invasion breadth as a standalone trigger for surgery simply because it now appears in a standardized pathology report. The value of routine measurement is currently more strategic. If pathologists begin recording breadth consistently, future multicentre datasets can determine whether it meaningfully improves prediction of lymph-node metastasis or other outcomes. Sometimes standardisation precedes validation. That is acceptable—as long as we remember which side of that line we are on. Margins: “Tumour on Ink” Provides a Cleaner Language Margin status is among the highest-stakes elements of an ESD pathology report. The consensus defines a positive margin as direct tumour contact with the inked resection surface. That “tumour on ink” approach provides a clear and reproducible definition. But reliable margin assessment begins long before the pathologist looks down the microscope. The specimen needs to be: pinned promptly properly oriented accurately inked completely embedded systematically sectioned ESD specimens can curl, retract, fragment, or develop substantial cautery artefact. If orientation is lost early, margin assessment later becomes much more difficult. When margin status is equivocal, deeper sections or adjunct immunohistochemistry may help. Again, the practical message is collaborative. The endoscopist cannot simply place the specimen in a container and assume pathology will reconstruct the anatomy by instinct. A little care at the beginning can prevent a great deal of uncertainty at the multidisciplinary meeting. A Narrow Negative Margin Is Not the Same as a Positive Margin The consensus also cautions against interpreting margin distance in isolation. A narrow but negative deep margin may carry different implications depending on the rest of the histology. If lymphovascular invasion, poor differentiation, extensive invasion, or other adverse features are absent, its significance may differ from the same margin in a biologically higher-risk lesion. Conversely, a positive deep margin in invasive carcinoma generally warrants escalation of treatment or multidisciplinary discussion. This reinforces a recurring theme throughout the paper: Risk after ESD is composite. The pathology report should help clinicians assemble that risk, not reduce it to one binary field. Stains Should Resolve Uncertainty, Not Manufacture Certainty The consensus maintains hematoxylin and eosin staining as the foundation of pathological assessment. Ancillary stains should be used selectively when conventional morphology is equivocal or compromised. Examples include difficult assessment of: lymphovascular invasion distorted muscularis mucosae invasion depth margin status For suspected lymphovascular invasion, stains such as D2-40, CD31/CD34, or elastic stains may help in selected cases. Smooth muscle or epithelial markers may assist when anatomical distortion makes invasion depth difficult to determine. This is a reassuringly balanced position. Immunohistochemistry is enormously useful when it answers a specific question. It becomes less useful when ordered simply because a stain exists. The consensus also recommends documenting why ancillary testing was performed and what final interpretation resulted. If the stain is unavailable or non-diagnostic, that limitation should be stated. A report saying “uncertain despite additional staining” may be less satisfying than a definitive answer, but it is considerably more useful than false certainty. Tumour Budding Deserves a Standardised Place in the Report The consensus recommends reporting tumour budding using International Tumour Budding Consensus Conference criteria. Reports should document the bud count in a standardized 20× field and provide the corresponding budding grade. H&E remains the preferred method for assessing budding, with immunohistochemistry reserved for difficult or equivocal cases. Tumour budding is not being introduced as an isolated decision-maker. Rather, it joins lymphovascular invasion, differentiation, histological subtype, perineural invasion, margin status, and invasion measurements as part of a broader risk profile. The panel also recommends describing mucinous and signet-ring cell carcinoma separately, rather than forcing them into the conventional grading framework used for tubular adenocarcinoma. That is a small reporting distinction with meaningful biological logic. Not every carcinoma behaves as though it belongs in the same histological box. The Pathology Report Should Function as a Clinical Tool One of the strongest messages in the consensus is that the post-ESD pathology report should not read like a collection of disconnected microscopic observations. It should provide the multidisciplinary team with the information required to decide what happens next. Depending on the findings, that may include: surveillance repeat endoscopic therapy additional staging surgical referral other treatment The pathology report therefore becomes a risk map. Its value is not simply in describing what the tumour looked like. Its value lies in telling the clinical team which adverse features are present, which are absent, how confidently they were assessed, and where uncertainty remains. That is particularly important for early cancers, where management decisions often sit close to the boundary between endoscopic cure and additional intervention. What the Consensus Does Not Prove The temptation with any international consensus is to treat agreement among experts as equivalent to proof. They are not the same thing. This study used modified Delphi methodology. That method is useful for areas where evidence is incomplete and expert standardisation is needed, but it remains dependent on panel composition, expert judgment, and response patterns. The consensus therefore does not prove that: every reporting variable independently predicts survival every recommendation reduces lymph-node metastasis invasion breadth should currently determine treatment a new universal post-ESD risk calculator has been validated standardised reporting by itself improves oncologic outcomes Those conclusions would exceed the evidence. The strongest claim is more practical. Standardised assessment should reduce reporting variability, improve communication, and provide better-quality data for future validation. That is a worthwhile objective in its own right. The Immediate Opportunity: Synoptic Reporting The most obvious implementation step is the development of structured or synoptic pathology templates. For invasive carcinoma following ESD, a report should reliably capture: submucosal invasion depth in micrometres invasion breadth in millimetres margin status using tumour-on-ink terminology lymphovascular invasion tumour budding tumour differentiation histological subtype perineural invasion ancillary stains performed relevant interpretive limitations For endoscopy units, implementation begins even earlier. Immediate pinning, orientation, specimen mapping, correct inking, and clear communication with pathology should become part of routine quality systems. In practical terms, the ESD is not completely finished when the knife is withdrawn. It is finished when the specimen has been handled well enough for pathology to answer the oncologic question reliably. Where the Evidence Needs to Go Next The consensus creates a framework. The next challenge is validation. Prospective multicentre studies should examine whether standardized reporting improves reproducibility between pathologists and whether individual or composite histological variables reliably predict lymph-node metastasis and other clinically meaningful outcomes. Invasion breadth particularly requires further evaluation. Synoptic templates could also support multicentre registries, allowing these pathological features to be recorded consistently enough for more robust risk models to emerge. That may be where the greatest long-term benefit lies. A standardized report today can become a better predictive model tomorrow—provided the data are collected consistently. Clinical Takeaway This international Gut consensus reframes pathology after ESD as part of the treatment decision rather than a descriptive exercise performed after the treatment is complete. The central message is practical. Submucosal invasion should be measured reproducibly. Margins should be defined clearly. Lymphovascular invasion, tumour budding, differentiation, histological subtype, perineural invasion, and other adverse features should be documented systematically. Ancillary stains should clarify genuine uncertainty. And none of these variables should be interpreted entirely in isolation. For gastroenterologists, the implication is equally important. High-quality ESD requires high-quality specimen handling and a pathology report capable of supporting an oncologic decision. The consensus is expert-based rather than trial-based, and some proposed parameters—particularly invasion breadth—still require prospective validation. But standardising the language and measurements used after ESD is a logical step toward more consistent multidisciplinary care. Once an early cancer has been removed, the pathology report is no longer merely a description of what was taken out. It becomes the map for deciding whether anything more needs to be done. Five Key Clinical Takeaways This is an international modified Delphi consensus, not a clinical outcomes trial. Its primary value is standardisation of post-ESD pathology reporting. Sm1–Sm3 classification should be reserved for specimens containing muscularis propria. Otherwise, submucosal invasion depth should be reported in micrometres. A positive margin is defined by direct tumour contact with the inked resection surface. Reliable assessment depends heavily on correct specimen handling and orientation. H&E remains the foundation of assessment. Ancillary stains should be used selectively when lymphovascular invasion, margins, or tissue anatomy are genuinely difficult to interpret. Post-ESD oncologic risk should be assessed using multiple histological variables together. Depth, margins, lymphovascular invasion, tumour budding, differentiation, and histological subtype should not be interpreted as isolated findings. Source Reference Khalaf K, Li H, Iwaya M, et al. Risk-based pathology reporting after endoscopic submucosal dissection for early gastrointestinal cancer: international consensus standards. Gut. Published online 10 July 2026. DOI: 10.1136/gutjnl-2025-337567.

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13 min readAug 8, 202615reads

IBS Beyond Symptoms: What Faecal Proteases and Enteric Neuronal Activation May Be Telling Us

When the Colonoscopy Is Normal but the Symptoms Clearly Are Not Anyone who has spent enough years in a gastroenterology clinic knows this consultation. The colonoscopy is normal. Routine blood tests offer little explanation. There is no obvious structural disease. Yet the patient sitting opposite you is describing urgency, abdominal pain, unpredictable bowel movements, and a quality of life that is anything but normal. In another room, a patient with constipation-predominant IBS may have equally disabling symptoms but an almost opposite bowel pattern. We classify both under irritable bowel syndrome. Clinically, that is useful. Biologically, it may be rather crude. The paper “Faecal proteases and immune signatures drive subtype-specific enteric neuronal activation in IBS,” published Online First in Gut in August 2026, asks whether something measurable in the intestinal lumen helps explain why IBS-D and IBS-C behave differently. The investigators studied whether faecal material from patients with IBS could directly activate enteric neurons and, importantly, whether the mechanism of that activation differed between diarrhoea-predominant and constipation-predominant disease. This was a translational mechanistic study. It was not a treatment trial. It was not designed to validate a diagnostic test for routine practice. And it certainly does not mean we should begin ordering stool protease panels on Monday morning. What it does provide is an intriguing biological bridge between the contents of the intestinal lumen and altered enteric neuronal signalling. For a disorder still defined largely by symptoms, that is worth examining carefully. Why Look at the Enteric Nervous System? The enteric nervous system is sometimes described as the gut's “second brain,” a phrase that has probably appeared on more patient-information leaflets than most of us care to count. The physiology behind the cliché, however, is important. Enteric neurons participate in the regulation of motility, secretion, vascular responses, sensory signalling, and communication between the mucosa and immune system. Submucous plexus neurons are particularly interesting because they sit close to the interface between luminal contents and mucosal function. IBS research has already implicated several biological processes, including altered epithelial permeability, visceral hypersensitivity, low-grade immune activity, microbial influences, and faecal protease activity. What has been less clear is whether mediators present in stool can directly alter enteric neuronal activity—and whether this differs between recognised IBS subtypes. That was the biological question behind this study. If stool-derived material from IBS patients activates enteric neurons more strongly than material from healthy individuals, it would support the existence of a functional lumen–enteric nervous system pathway. It would not solve IBS. But it would move the discussion one step beyond describing symptoms. What the Investigators Actually Did According to the accessible abstract, investigators analysed faecal supernatants from: 21 patients with IBS-D 9 patients with IBS-C 18 healthy controls Participants were recruited across centres in three countries. The faecal supernatants were applied to submucous plexus neurons from guinea pig distal colon , and neuronal activation was measured using neuroimaging techniques. The investigators also examined faecal proteolytic activity and performed proteomic profiling. This design deserves some attention because it determines how far the findings can reasonably be taken. The exposure was not a drug or a dietary intervention. It was the soluble material present in stool from different clinical groups. The researchers were essentially asking whether that luminal material could provoke a measurable neuronal response under controlled experimental conditions. That is a useful mechanistic experiment. But guinea pig enteric neurons exposed experimentally to human stool supernatant are not the same thing as a patient experiencing IBS symptoms in vivo. The model allows us to study biological plausibility. It does not reproduce the entire human disorder. Both IBS Subtypes Activated Neurons—But Through Different Routes One of the central findings was that faecal supernatants from both IBS-D and IBS-C patients produced significantly greater enteric neuronal activation than supernatants from healthy controls. That observation alone is interesting. It suggests that the stool of patients with IBS contains soluble mediators capable of influencing enteric neuronal behaviour. The more important finding, however, was that the apparent mechanism differed between the two IBS subtypes. In IBS-D , neuronal activation was linked to: serine proteases cysteine proteases protease-activated receptor-1, or PAR-1 In IBS-C , increased neuronal activation was also observed, but it appeared to occur independently of the same protease/PAR-1 pathway. That distinction is arguably the most important contribution of the paper. IBS-D and IBS-C may share a general phenomenon—enhanced luminal activation of enteric neurons—while reaching that endpoint through different molecular pathways. For clinicians accustomed to seeing IBS represented as one large diagnostic category divided mainly by stool form, that is an intellectually useful shift. The bowel habit may be the visible phenotype. The biology underneath it may be considerably less uniform. Proteases May Be Participants, Not Merely Passengers Proteases are enzymes that cleave proteins, and the gastrointestinal lumen contains plenty of them. Their sources may include pancreatic secretion, host tissues, inflammatory cells, microbial activity, and other luminal processes. Faecal serine and cysteine protease activity has previously attracted attention in IBS because of possible associations with epithelial barrier dysfunction and visceral hypersensitivity. This study extends that conversation toward the enteric nervous system. In IBS-D, inhibition experiments implicated protease activity and PAR-1 in the neuronal response generated by faecal supernatants. That is more informative than simply finding that protease concentrations differ between groups. It suggests a functional pathway through which luminal proteolytic activity may influence neuronal signalling. The distinction between association and mechanism , however, remains important. The study supports a mechanistic role for proteases in an experimental system. It does not establish that proteases are the sole—or even dominant—cause of symptoms in every patient with IBS-D. It also does not demonstrate that inhibiting those proteases will improve pain, urgency, stool frequency, or quality of life. That therapeutic leap remains to be tested. A Subtle Immune Signal in IBS-D Proteomic analysis added another layer. The investigators reported significant differences in 47 proteins between IBS-D patients and healthy controls. Several of these involved immunoglobulin components. The authors interpreted these findings as compatible with an immune-enriched or microinflammatory faecal signature. This requires careful language. IBS is not inflammatory bowel disease. Nothing in this study suggests that IBS-D should suddenly be viewed as a mild form of ulcerative colitis or Crohn's disease. The term microinflammation refers here to subtle immune-associated molecular signals—not macroscopic inflammation, ulceration, or the structural tissue injury we associate with IBD. This may help explain an experience clinicians encounter frequently: patients can have substantial symptoms despite normal conventional structural testing. “Normal colonoscopy” does not necessarily mean “nothing biological is happening.” Nor, of course, does every detectable molecular difference automatically become clinically important. The challenge is determining which signals genuinely contribute to symptoms and which simply travel alongside them. Could These Signals Become Biomarkers? The study also identified a combination involving amylases, trypsin-2, and an immunoglobulin protein that showed high diagnostic performance in distinguishing IBS-D from healthy controls. For anyone who manages IBS regularly, the attraction is obvious. IBS remains primarily a clinical diagnosis. A biological marker reflecting disease mechanism rather than nonspecific inflammation would be valuable. A stool-based panel that helped identify a particular IBS-D phenotype could eventually support more objective disease stratification. Eventually is the important word. This study does not establish a clinically validated diagnostic assay. The study population was small, particularly the IBS-C group. Diagnostic performance derived from a discovery cohort can look impressive and then diminish considerably when tested in different populations. A clinically useful biomarker would need to work not only against healthy volunteers but against patients with the conditions clinicians actually struggle to distinguish from IBS-D. That includes inflammatory disease, infection, bile acid diarrhoea, malabsorption, medication-related diarrhoea, and other gastrointestinal disorders. A biomarker that separates IBS-D from perfect health is scientifically interesting. A biomarker that helps us manage the patient in front of us is a higher bar. What This May Tell Us About IBS-D For IBS-D, the study offers a reasonably coherent mechanistic model. Faecal material contains proteolytic and immune-associated signals. Those signals can activate enteric neurons experimentally. Part of that neuronal activation appears to involve serine and cysteine proteases and PAR-1. Biologically, one can see why this attracts attention. Enhanced neuronal activation could potentially contribute to phenomena familiar in IBS-D—urgency, altered sensory processing, abnormal secretion, and symptom fluctuations despite an absence of structural disease. But this remains a hypothesis supported by experimental data, not a clinical treatment pathway. The study does not demonstrate that: protease inhibition improves IBS-D symptoms PAR-1 blockade is an effective therapy all patients with IBS-D share the same protease signature stool protease measurement can guide treatment selection established IBS-D therapies should be replaced The proper interpretation is that the study identifies a plausible mechanistic pathway worthy of therapeutic investigation. That is already valuable. There is no need to make it promise more. IBS-C May Be the More Interesting Unfinished Story IBS-C deserves equal attention. Faecal material from IBS-C patients also produced greater neuronal activation than material from healthy controls. But that activation did not appear to depend on the same protease/PAR-1 mechanism identified in IBS-D. That finding is useful precisely because it leaves a question unanswered. What is activating those neurons in IBS-C? This study does not provide a definitive answer. Other luminal mediators may be involved, but the source does not establish which ones. It would therefore be premature to fill the gap with speculation about metabolites, bile acids, microbial products, or other candidate pathways. What the paper does show is simpler and more defensible: The neuronal activation observed in IBS-C appears biologically distinct from the protease-dependent pathway identified in IBS-D. The smaller IBS-C sample—only nine patients in the accessible abstract—also means that this observation should be regarded as exploratory. Still, it is an important warning against assuming that mechanisms discovered in diarrhoea-predominant IBS automatically apply to constipation-predominant disease. Clinical labels sometimes share a surname while having rather different relatives underneath. Why the Study Design Is Strong Several aspects of the study strengthen its biological argument. First, the investigators used human faecal material from clinically characterised IBS-D and IBS-C patients. Second, they measured functional neuronal activation , rather than stopping at static molecular associations. Third, they combined those functional experiments with measurements of protease activity and proteomic profiling. Fourth, they analysed IBS-D and IBS-C separately rather than treating IBS as a single biological entity. That integration is important. Finding a different protein concentration in stool is interesting. Showing that stool-derived material produces a neuronal response—and then investigating which molecular pathways contribute to that response—provides a more coherent mechanistic story. That remains a laboratory story for now. But it is a stronger one. Where We Need to Be Cautious There are several reasons not to move too quickly from these findings to clinical practice. The neuronal model was not human The experiments used guinea pig distal colon submucous plexus neurons. This is an established way to study enteric neuronal responses, but it cannot reproduce the complete physiology of the human gastrointestinal tract. The sample was small The accessible abstract describes 21 IBS-D patients, nine IBS-C patients, and 18 healthy controls. Those numbers may be sufficient for exploratory mechanistic work but are far from adequate for definitive clinical phenotyping or diagnostic validation. Stool composition is influenced by many variables Diet, medication, microbiome composition, transit time, host immune activity, and other environmental or biological factors can influence faecal proteins and proteolytic activity. The study does not establish how stable these signatures are over time. Neuronal activation is not the same as symptom causation Demonstrating that a faecal supernatant activates neurons experimentally does not prove that the same pathway explains abdominal pain, urgency, stool frequency, bloating, or the entire clinical IBS phenotype. The proposed biomarkers remain investigational The reported protein combination is a research finding. It is not ready for routine stool testing or clinical decision-making. What Clinicians Should Not Conclude This study does not show that IBS-D is simply a protease disorder. It does not show that IBS-C has now been mechanistically explained. It does not justify faecal protease testing in routine gastroenterology practice. It does not establish PAR-1 inhibition as treatment. And it does not make current dietary, pharmacological, behavioural, or other established IBS management approaches obsolete. Those conclusions would travel substantially further than the evidence. A more appropriate interpretation is that IBS subtypes appear capable of generating biologically distinct stool-derived signals that influence enteric neuronal activity. For a condition historically defined largely by symptoms, that is meaningful progress. It is not yet a prescription. The Larger Question: Are We Moving Toward Biological IBS Subtypes? Perhaps the most interesting implication of this work is not one particular protease or one potential stool biomarker. It is the possibility that the familiar IBS-D and IBS-C labels may eventually sit on top of more specific biological phenotypes. At present, treatment remains largely symptom-directed. A future approach might classify patients according to combinations of luminal mediators, microbial function, immune activity, neural sensitivity, epithelial barrier characteristics, and clinical phenotype. That possibility is attractive. But gastroenterology has seen many promising biomarkers arrive early and leave quietly. The next steps therefore matter enormously. The proteomic findings need independent replication. The neuronal findings need confirmation. The proposed biomarkers need validation in larger and more diverse populations. Researchers need to determine whether these molecular signatures correlate with clinically important outcomes such as: abdominal pain urgency stool frequency visceral hypersensitivity symptom severity treatment response Longitudinal studies would also be useful. Do these protease and immune signatures fluctuate when symptoms worsen? Do they normalise when patients improve? Or are they stable traits identifying biologically distinct subgroups? Those questions will determine whether these findings become clinically useful or remain elegant mechanistic observations. From Mechanism to Treatment Will Require Another Step The study also opens an obvious therapeutic question. If protease/PAR-1 signalling contributes meaningfully to IBS-D biology, could that pathway be targeted? Possibly. But mechanistic plausibility is not therapeutic efficacy. Interventional studies would need to identify the correct patient population, demonstrate target engagement, and—most importantly—show improvement in outcomes that matter to patients. A pathway can look beautiful on a laboratory diagram and still disappoint in the clinic. Gastroenterology has provided us with enough examples to remain appropriately humble. The same principle applies to biomarker development. Before a faecal protein panel becomes useful, researchers will need to demonstrate that it adds something beyond careful clinical assessment and that it performs well against relevant competing diagnoses. Only then does mechanistic elegance become clinical utility. Clinical Takeaway This Gut study provides experimental evidence that faecal mediators from patients with IBS can activate enteric neurons more strongly than faecal material from healthy controls. More importantly, the mechanism appears to differ by subtype. In IBS-D, neuronal activation was associated with serine and cysteine proteases and PAR-1, alongside an immune-enriched faecal proteomic signature. IBS-C faecal supernatants also increased neuronal activation, but apparently through a different and currently undefined pathway. For practicing gastroenterologists, this should not change tomorrow's treatment algorithm. IBS remains a clinical diagnosis, and the proposed faecal biomarkers are not ready for routine testing. The value of the study is more fundamental. It strengthens the argument that IBS-D and IBS-C may represent biologically distinct disorders beneath their symptom-based labels—and that stool-derived signals can interact directly with the enteric nervous system. That brings us closer to a mechanistic understanding of IBS. Whether it eventually brings us better biomarkers or more targeted treatments will require much larger and more clinically oriented studies. For now, the appropriate response is interest without overenthusiasm. In IBS research, that is usually a sensible place to stand. Five Key Clinical Takeaways The study is mechanistic, not a clinical trial. Human faecal supernatants were tested on enteric neurons to investigate biological pathways underlying IBS subtypes. Both IBS-D and IBS-C stool-derived mediators increased neuronal activation. This supports a potential lumen–enteric nervous system signalling pathway in IBS. IBS-D showed a distinct protease-related mechanism. Serine and cysteine proteases and PAR-1 were implicated in neuronal activation, whereas IBS-C activation appeared independent of this pathway. The faecal proteomic findings are promising but preliminary. A candidate protein combination showed diagnostic potential for IBS-D, but it is not a validated clinical test. Nothing here justifies changing current IBS management. The study supports biological subtyping and future biomarker and therapeutic research, not immediate changes to diagnosis or treatment. Source Reference Ridžal L, Frieling T, Róka R, et al. Faecal proteases and immune signatures drive subtype-specific enteric neuronal activation in IBS. Gut. Online First, August 2026.

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10 min readAug 7, 202613reads

Disaggregating Hepatocellular Carcinoma Risk: What an EHR-Based Cohort Reveals About Racial and Ethnic Disparities

The Problem With “Asian,” “Hispanic,” or “Black” as Single Risk Categories Hepatocellular carcinoma risk is rarely distributed evenly across a population. Clinicians see this every day: patients with chronic hepatitis B, hepatitis C, metabolic dysfunction-associated fatty liver disease, alcohol-related liver disease, cirrhosis, immigration-related viral hepatitis risk, and uneven access to surveillance do not fit neatly into broad epidemiologic labels. Yet much of the research literature and many health-system dashboards still group patients into large racial or ethnic categories that may conceal clinically meaningful differences. The article “Detailed racial/ethnic disparities in hepatocellular carcinoma risk with an electronic health record-based cohort” by DeRouen and colleagues was listed in Clinical Gastroenterology and Hepatology as an Article in Press in early August 2026. The official journal listing identifies the article title and first author, and a ScienceDirect listing describes the study question as assessing sex-specific disparities in hepatocellular carcinoma risk according to detailed race and ethnicity within a multi-institutional electronic health record cohort. The available detailed abstract from the same EHR-based cohort describes a large linked cohort assembled from three health care systems, with race and ethnicity characterized into more granular groups, then linked to cancer registry data for incident HCC. This is observational epidemiology, not an intervention trial. It should therefore be interpreted as evidence of associations and disparity patterns, not as proof that race or ethnicity itself causes HCC. What the Study Set Out to Clarify The study question is important because HCC disparities have been recognized for years, but broad race and ethnicity categories can obscure heterogeneity within populations. “Asian American/Pacific Islander,” for example, can combine groups with different HBV prevalence, migration histories, language barriers, socioeconomic exposures, health-system access, and surveillance uptake. A single category may be statistically convenient but clinically blunt. According to the accessible cohort abstract, the investigators assembled a pooled electronic health record-based cohort linked to population-based cancer registries. The aim was to examine disparities in HCC risk across detailed racial and ethnic groups and to explore the relative contribution of known and putative HCC risk factors, including smoking, hepatitis infections, and metabolic syndrome. The clinical value lies in the level of detail. For hepatologists and gastroenterologists, the question is not simply whether disparities exist. The more actionable question is whether aggregated categories hide high-risk subgroups who may require more targeted prevention research, better viral hepatitis identification, improved surveillance outreach, and culturally appropriate health-system interventions. A Large EHR-Registry Linkage, Not a Conventional Clinic Cohort The cohort described in the accessible abstract included adults with at least one in-person encounter between 2000 and 2017 within three health care systems: San Francisco Health Network, Sutter Health Northern California, and Kaiser Permanente Hawai’i. EHR data were linked to population-based state cancer registry data to identify incident HCC. The cohort included 4,249,671 adults , with a median follow-up of 6.8 years ; 55% were female , and 2,916 incident HCC cases were identified. This design has clear strengths. First, the sample size is large enough to examine subgroups that would be invisible or underpowered in smaller cohorts. Second, linkage to cancer registry data strengthens ascertainment of incident HCC compared with relying only on diagnosis codes within a single health system. Third, use of EHR data allows investigators to incorporate clinical and sociodemographic variables not always available in cancer registries. But the design also carries limitations. EHR cohorts are shaped by who enters the health system, how often they receive care, how diagnoses are coded, and how race and ethnicity are recorded. A person’s documented racial or ethnic category is not a biologic exposure; it is a social, demographic, administrative, and sometimes imperfectly captured variable. Therefore, the findings should be used to identify disparities and research needs, not to biologize race or to assign deterministic risk to individuals. The Exposure Was Detailed Race and Ethnicity—But the Outcome Was Incident HCC The main exposure of interest was detailed racial and ethnic classification, derived from EHR data. The investigators used EHR information to define 17 detailed racial and ethnic groups , alongside other sociodemographic and clinical factors. They used Cox proportional hazards regression with age as the time scale and sex-specific models adjusted for length of active follow-up, with stratification by site, birth cohort, baseline year, and number of encounters. They also calculated sex-specific hazards and population attributable fractions for HCC risk factors among racial and ethnic groups. The outcome was incident hepatocellular carcinoma identified through linked cancer registry data. This distinction matters because the study was not evaluating treatment response, survival, surveillance adherence, transplant referral, or liver-related mortality. It was focused on HCC risk occurrence in a very large, diverse, real-world cohort. For clinicians, this means the findings should primarily inform thinking about risk stratification, prevention research, surveillance equity, and public health targeting. They do not by themselves answer whether a particular subgroup should undergo surveillance outside established guideline indications. The Most Striking Signal: Vietnamese American Patients Had the Highest Relative Risk Reported The accessible abstract reports that, compared with non-Hispanic White males, Vietnamese American males had greater HCC risk , with a hazard ratio of 7.42 and 95% confidence interval 4.25–12.96 . Increased risk was also reported among American Indian/Alaska Native, Black, Chinese American, Hispanic, Native Hawaiian, Pacific Islander males, and males of multiple races or ethnicities. Among females, nearly every group except American Indian/Alaska Native, Asian Indian American, and Pacific Islander females had higher HCC risk than non-Hispanic White females. Reported hazard ratios ranged from 1.68 among Filipino females to 6.38 among Vietnamese American females. The clinical interpretation should be cautious but attentive. These hazard ratios indicate associations within this cohort after the specified modeling approach. They do not mean that Vietnamese ethnicity itself causes HCC. Rather, they likely reflect a combination of underlying liver disease burden, viral hepatitis epidemiology, migration history, structural determinants, health care access, surveillance patterns, and other measured or unmeasured factors. For GastroAGI readers, the practical message is that broad categories can be misleading. A clinician looking only at “Asian American” as a single category may miss the magnitude of risk observed in some subgroups while overgeneralizing risk to others. Why Disaggregation Matters for Hepatology Practice Hepatologists already practice a form of individualized risk assessment. We ask about HBV status, HCV history, cirrhosis, MASLD, alcohol use, family history, country of birth, prior antiviral therapy, fibrosis stage, and surveillance adherence. Yet health systems often operationalize equity work through broad demographic fields that are too coarse for targeted prevention. This study strengthens the argument that disaggregated data are clinically and epidemiologically important. If health systems cannot distinguish between detailed Asian American, Native Hawaiian, Pacific Islander, Hispanic, American Indian/Alaska Native, Black, and multiracial groups, they may fail to identify where HCC prevention efforts are most needed. That does not mean race or ethnicity should replace clinical risk factors. It means these variables may help identify where risk factors cluster, where screening gaps persist, and where outreach needs cultural, linguistic, or system-level adaptation. Risk Factors Did Not Behave as a Single Uniform Story The abstract reports that HCC risk according to clinical risk factors was broadly similar for males and females, but one notable difference was observed: the population attributable fraction of HCC for alcohol disorders was much higher for females than males in the available analysis. The abstract reports a PAF of 43% for females compared with 2% for males . It also notes variation in factor-specific HCC risk by racial and ethnic group in preliminary analyses. For example, metabolic-associated fatty liver disease and ever-smoking were associated with greater HCC risk only among non-Hispanic White and Asian American males in preliminary subgroup analyses. These observations should not be overinterpreted. Population attributable fractions depend on both the strength of association and the prevalence of the exposure in the studied population. They are not individual-level risk predictions. They also depend on how alcohol disorders, metabolic syndrome, MAFLD, viral hepatitis, and smoking were captured in EHR data. Still, the broader point is highly relevant: the drivers of HCC disparities may not be identical across groups. If viral hepatitis, metabolic risk, alcohol-related liver disease, and surveillance access contribute differently across populations, then a single prevention message is unlikely to be sufficient. What Clinicians Should Conclude Clinicians can reasonably conclude that this study supports more granular assessment of HCC disparities. It reinforces the need to avoid assuming that broad race and ethnicity categories are clinically homogeneous. It also supports the use of linked EHR and cancer registry data as a powerful method to identify population-level disparity patterns. The study may influence practice indirectly by encouraging health systems to improve race and ethnicity data capture, stratify HCC prevention metrics more precisely, and examine whether surveillance eligibility and surveillance completion differ across detailed subgroups. However, clinicians should not conclude that the study creates new surveillance indications based on race or ethnicity alone. Current HCC surveillance decisions should still be anchored in established risk conditions such as cirrhosis, chronic HBV infection in guideline-defined risk groups, and other validated clinical criteria. This study is best understood as a health-equity and epidemiologic signal that may guide future research and implementation strategies. What the Study Cannot Prove The study cannot prove causation. Race and ethnicity are not biologic mechanisms. They are markers that may correlate with ancestry, migration, geography, viral hepatitis exposure, socioeconomic context, structural racism, language access, insurance status, health-system engagement, neighborhood factors, and clinical risk profiles. The EHR-based design also means that risk factor measurement may be incomplete. Alcohol disorders, smoking, viral hepatitis status, metabolic syndrome, and MAFLD can be undercoded or inconsistently documented. Patients with more encounters may have more complete ascertainment of risk factors. Conversely, patients with limited access or fragmented care may have under-recorded exposures. Another limitation is generalizability. The cohort came from three health care systems in California and Hawai’i. These settings are highly relevant for studying diverse populations, but findings may not directly generalize to every US region, rural population, uninsured population, or international setting. Finally, the article’s detailed full text should be reviewed before translating its findings into institutional policy. The accessible data strongly support the concept of disaggregation, but local implementation requires careful attention to data quality, community engagement, and current surveillance guidelines. Implications for Future Research and Implementation The most important next step is not simply to replicate hazard ratios. It is to understand what lies behind them. Future studies should clarify the relative contribution of HBV, HCV, MASLD, alcohol-related liver disease, cirrhosis, socioeconomic position, language access, immigration history, health-system utilization, and surveillance completion across detailed racial and ethnic groups. Health systems should also examine whether their EHR race and ethnicity fields are adequate for disparity research. If categories are too broad, inconsistently collected, or not patient-reported, risk patterns may remain hidden. The related abstract on race and ethnicity characterization in this cohort emphasized that researchers must critically assess racial and ethnic categories typically available from healthcare system repositories and use schemas that avoid masking smaller populations. For clinicians and researchers, the implementation challenge is to translate epidemiologic insight into equitable care without stereotyping. That means using disaggregated data to identify populations who may benefit from better viral hepatitis testing, linkage to care, fibrosis assessment, surveillance navigation, language-concordant education, and culturally informed outreach. Clinical Takeaway This EHR-linked cohort study highlights a central problem in HCC disparities research: broad racial and ethnic categories can conceal clinically meaningful heterogeneity. Vietnamese American patients showed particularly high relative HCC risk in the accessible cohort data, and several other detailed groups also had elevated risk compared with non-Hispanic White reference groups. These are associations, not proof of causation. For gastroenterologists and hepatologists, the study should not be interpreted as creating race-based surveillance recommendations. Its value is different: it argues for better data granularity, better understanding of subgroup-specific risk drivers, and more precise prevention strategies. The future of equitable HCC prevention will likely depend not only on knowing who has cirrhosis or viral hepatitis, but also on whether our health systems can identify and reach the communities in whom preventable liver cancer risk remains concentrated. Five Key Clinical Takeaways The verified article is “Detailed racial/ethnic disparities in hepatocellular carcinoma risk with an electronic health record-based cohort,” listed in Clinical Gastroenterology and Hepatology as an Article in Press in early August 2026. The study used a large EHR-based cohort linked to cancer registry data to assess incident HCC risk across detailed racial and ethnic groups. The accessible cohort abstract included 4,249,671 adults, median follow-up 6.8 years, and 2,916 incident HCC cases. Vietnamese American males and females had the highest relative HCC risk reported in the accessible abstract compared with non-Hispanic White reference groups. The study supports more granular disparity research and targeted prevention planning, but it does not establish new race-based clinical surveillance guidance. Source Reference and Link DeRouen MC, Thompson CA, and colleagues. Detailed racial/ethnic disparities in hepatocellular carcinoma risk with an electronic health record-based cohort. Clinical Gastroenterology and Hepatology. Article in Press, early August 2026. Official article listing: Supporting accessible cohort abstract from the same research program: DeRouen MC et al. Examining factors that contribute to racial and ethnic disparities in liver cancer within an EHR-based epidemiologic cohort linked to cancer registries. Cancer Epidemiology, Biomarkers & Prevention. 2023;32(12 Suppl) B138.

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13 min readAug 7, 202630reads

Risk-Based Gastric Cancer Surveillance: What the AGA Clinical Practice Update Means in Everyday Gastroenterology

When a Small Biopsy Finding Creates a Large Clinical Question Few pathology reports generate quite as much uncertainty as an incidental diagnosis of gastric atrophy, intestinal metaplasia, or dysplasia. The patient may feel entirely well. The endoscopy may have been performed for an unrelated indication. Yet the biopsy report suddenly introduces the possibility of future gastric cancer risk—and with it, a series of questions that are not always easy to answer. Does this patient need another endoscopy? How extensively should the stomach be biopsied? Does every patient with gastric intestinal metaplasia require surveillance? And perhaps most importantly, are we dealing with a meaningful premalignant condition or simply a histologic finding whose clinical significance has not yet been adequately defined? These questions are particularly relevant in the United States, where population-wide gastric cancer screening is not routine, but risk is far from evenly distributed. The American Gastroenterological Association Clinical Practice Update by Shah, Wang, Wallace, and Hwang attempts to bring greater structure to this area. Published in Gastroenterology in February 2025, following online publication on December 23, 2024, the document provides best practice advice on screening and surveillance for individuals at increased risk of gastric cancer in the United States. It is important to be precise about what kind of document this is. This is a Clinical Practice Update Expert Review. It is not a randomized controlled trial, a cohort study, or a formally graded clinical guideline. The advice statements were developed through review of the published literature and expert opinion. A formal systematic review was not performed, and the recommendations do not carry graded ratings of evidence quality or strength. That distinction is not academic housekeeping. It determines how the document should be used. The CPU is best understood as a practical clinical framework for a difficult and inconsistently managed problem—not as a universal mandate for gastric cancer screening. The Cancer Pathway the Update Is Trying to Interrupt The primary focus is intestinal-type noncardia gastric adenocarcinoma, referred to throughout the update as gastric cancer. This cancer pathway is closely associated with chronic Helicobacter pylori infection and the progressive development of premalignant gastric mucosal changes, including atrophic gastritis, gastric intestinal metaplasia, dysplasia, and eventually carcinoma. Autoimmune gastritis may also arise within the broader clinical landscape of premalignant gastric disease. However, the CPU does not attempt to provide detailed guidance on every related condition. Comprehensive management of autoimmune gastritis, gastric intestinal metaplasia, endoscopic submucosal dissection, and post-resection care is directed to other AGA publications. The underlying clinical problem is familiar: premalignant gastric conditions are usually silent. Early gastric cancer is also frequently asymptomatic. Waiting for pain, weight loss, anaemia, or obstructive symptoms is therefore not an effective prevention strategy. By the time the stomach complains loudly, it may already have been quiet for far too long. In current US practice, endoscopy with histologic confirmation remains the method by which gastric premalignant conditions and early gastric cancer can be diagnosed accurately. The practical question is therefore not whether every person should undergo screening. It is whether a particular patient carries enough baseline risk to justify a carefully performed endoscopic assessment. Who Should Enter the Screening Conversation? The CPU identifies several groups in the United States who should be considered for gastric cancer screening: First-generation immigrants from regions with a high incidence of gastric cancer Possibly other non-White racial and ethnic groups Individuals with a first-degree family history of gastric cancer Patients with selected hereditary gastrointestinal polyposis or hereditary cancer syndromes These categories identify people who may deserve consideration for screening. They do not create a single surveillance pathway for everyone within them. A first-generation immigrant from a high-incidence region, a patient with a strong family history, and a person with a hereditary cancer syndrome may all enter the discussion through different doors. What happens after that depends heavily on the findings at the index endoscopy. Risk is subsequently refined through endoscopic and histologic staging. Important features include: The presence and severity of atrophic gastritis The presence and anatomical distribution of gastric intestinal metaplasia Active or previous H pylori infection Histologic subtype of intestinal metaplasia, when applicable The presence of dysplasia Additional familial, demographic, or hereditary risk factors This is one of the most useful aspects of the CPU. Demographic or familial risk may determine who enters the screening pathway. The quality of the endoscopic and pathological assessment then determines whether that patient should remain in a surveillance programme. The Index Endoscopy Must Do More Than Reach the Duodenum The CPU identifies endoscopy as the best screening and surveillance test for individuals at increased risk of gastric cancer. That conclusion is not based merely on the ability to look inside the stomach. A properly performed examination allows the endoscopist to identify subtle mucosal abnormalities, target suspicious lesions, obtain systematic biopsies, and establish the distribution and severity of premalignant disease. In this context, endoscopy is not simply a diagnostic procedure. It is the platform on which subsequent risk stratification is built. The CPU therefore places considerable emphasis on examination quality, including: High-definition white-light endoscopy Image-enhanced endoscopy Adequate mucosal cleansing Appropriate gastric insufflation Careful inspection Photodocumentation Systematic biopsy protocols when indicated This has an immediate practical implication. A report stating that the “stomach appeared normal” is not necessarily equivalent to a high-quality negative gastric cancer screening examination. The value of the conclusion depends on how thoroughly the stomach was cleaned, distended, inspected, documented, and sampled. The same applies to pathology. A few randomly obtained fragments placed into a single jar may confirm that intestinal metaplasia exists, but they may not establish where it exists or how extensive it is. And without anatomical extent, meaningful risk stratification becomes difficult. Gastric Biopsies Need Geography For suspected gastric atrophy, with or without intestinal metaplasia, the CPU advises systematic biopsy sampling using a protocol such as the updated Sydney System. At least five biopsies should be obtained. Samples from the antrum and incisura should be placed together in one labelled container, while samples from the gastric corpus should be placed in a separate container. Any visually suspicious lesion should be described and biopsied separately. This may sound like a small technical detail. It is not. Separate anatomical labelling allows the pathologist to determine whether disease is limited or extensive. That distinction can materially influence surveillance decisions. Focal changes confined to one region do not necessarily carry the same implications as multifocal or extensive atrophy or intestinal metaplasia involving both the distal and proximal stomach. In other words, gastric biopsies need a map—not merely a jar. The CPU also encourages collaboration between endoscopists and local gastrointestinal pathologists. When atrophic gastritis or intestinal metaplasia is identified, pathology reports should consistently document clinically useful risk-stratification features. At minimum, these include: Presence or absence of H pylori Severity of gastric atrophy and/or intestinal metaplasia Histologic subtype of intestinal metaplasia, when applicable This is a valuable quality-improvement opportunity for many centres. Surveillance decisions can only be as reliable as the endoscopic sampling and pathology reporting on which they are based. When either is incomplete, the apparent precision of the follow-up plan may be misleading. H pylori Eradication Is Foundational—but Not the Whole Strategy The CPU positions H pylori eradication as an essential component of both primary and secondary gastric cancer prevention. Opportunistic testing for H pylori should be considered in individuals judged to be at increased risk of gastric cancer. The document also supports considering testing of adult household members when an individual is found to be infected, reflecting a family-based approach to detection. For clinicians, the key word is foundational. Eradication of active H pylori is central to prevention, but it should not be mistaken for a substitute for endoscopic assessment in patients who already have significant premalignant mucosal abnormalities or suspected neoplasia. The CPU specifically notes that eradication should not delay necessary endoscopic intervention. This distinction matters in practice. Treating H pylori addresses an important carcinogenic driver. It does not automatically remove the need to stage the mucosa, evaluate dysplasia, or investigate a suspicious lesion. Once advanced atrophy, extensive intestinal metaplasia, or dysplasia is present, the clinical conversation has moved beyond infection treatment alone. What Happens After a Negative Index Examination? The CPU offers a pragmatic approach when an increased-risk patient undergoes screening endoscopy and no atrophy, intestinal metaplasia, or neoplasia is identified. Further screening should not be automatic. It should be considered in the context of the individual’s underlying risk factors and preferences. Continued screening may be reasonable in those with a family history of gastric cancer or several concurrent risk factors. However, the optimal interval after a negative index examination remains uncertain. This is an area where the document is appropriately cautious. A high-quality negative examination may be reassuring, but it does not necessarily eliminate future risk in someone with strong familial, hereditary, or demographic predisposition. At the same time, the CPU does not provide evidence for repeating endoscopy at a fixed interval in every such patient. Shared decision-making is therefore unavoidable. The clinician must weigh the quality of the original examination, the patient’s baseline risk, comorbidities, preferences, and the uncertainty surrounding potential benefit. Which Premalignant Findings May Justify Surveillance? For patients with confirmed gastric atrophy, with or without intestinal metaplasia, the CPU recommends further risk stratification rather than treating all findings as equivalent. Patients with severe atrophic gastritis and those with multifocal or incomplete gastric intestinal metaplasia are considered more likely to benefit from surveillance, particularly when additional risk factors such as a family history of gastric cancer are present. This is where careful wording matters. The CPU uses these findings as risk markers supporting consideration of surveillance. It does not demonstrate through randomized evidence that a particular surveillance interval reduces gastric cancer mortality in every subgroup. Clinicians should therefore resist two extremes. The first is dismissing all gastric intestinal metaplasia as an incidental biopsy finding of little consequence. The second is placing every patient with intestinal metaplasia into indefinite endoscopic surveillance without considering extent, subtype, examination quality, competing risks, or patient preferences. The more defensible position lies between those approaches: stage carefully, identify the higher-risk phenotype, and individualize the surveillance decision. Dysplasia Is Not a Routine Follow-Up Finding The CPU treats gastric dysplasia as a distinctly higher-risk clinical problem. Both indefinite and low-grade dysplasia may be difficult to identify reliably at endoscopy and may also be challenging to diagnose consistently on histopathology. For that reason, all gastric dysplasia should be confirmed by an experienced gastrointestinal pathologist. Patients with either visible or nonvisible dysplasia should be referred to an endoscopist or centre with expertise in the diagnosis and management of gastric neoplasia. This is an important escalation point. Dysplasia should not simply trigger another routine endoscopy placed somewhere on a general waiting list. It requires confirmation, careful reassessment, appropriate image-enhanced examination, and access to clinicians familiar with subtle gastric neoplasia. For suspected high-grade dysplasia or early gastric cancer, the CPU advises endoscopic submucosal dissection with the goal of en bloc, R0 resection. This permits accurate pathological staging and, where appropriate, treatment with curative intent. Patients who undergo successful resection of gastric dysplasia or cancer require continued endoscopic surveillance. The CPU also acknowledges that further evidence is needed to determine the most appropriate surveillance strategies, particularly within US populations. Surveillance Has Little Value When Treatment Is No Longer Possible One of the most clinically mature recommendations in the CPU concerns when surveillance should stop. Screening and surveillance should be offered only to patients who are sufficiently fit to undergo endoscopic or potentially surgical treatment if clinically important neoplasia is found. When a patient is no longer a candidate for meaningful intervention, surveillance should be discontinued. This avoids a common problem in preventive medicine: continuing a test long after its result can no longer improve the patient’s care. The purpose of surveillance is not simply to detect disease earlier. It is to detect disease at a point when the patient can benefit from treatment. The CPU does not impose a strict age threshold or a single comorbidity cutoff. Instead, clinicians are asked to consider life expectancy, frailty, procedural risk, fitness for treatment, competing health priorities, and patient preference. A surveillance programme should have a plausible clinical destination. Otherwise, it risks becoming an annual ritual rather than a meaningful intervention. What This Update Changes in Practice The CPU supports a more structured approach to gastric cancer prevention in higher-risk US populations. Its practical pillars are: Identifying individuals with increased baseline risk Performing a genuinely high-quality index endoscopy Mapping premalignant gastric changes through systematic biopsies Ensuring pathology reports contain clinically useful staging information Detecting and eradicating H pylori Escalating dysplasia to experienced pathology and endoscopy teams Individualizing surveillance according to mucosal findings and patient-level risk Stopping surveillance when treatment would no longer be appropriate Perhaps the most important shift is conceptual. The CPU does not treat gastric cancer surveillance as a simple yes-or-no decision based on the presence of intestinal metaplasia. It treats surveillance as the final step in a sequence that begins with patient selection and depends on the quality of everything that follows. Poor patient selection, hurried endoscopy, unmapped biopsies, and vague pathology cannot be rescued by choosing a precise surveillance interval at the end. What Clinicians Should Not Read Into the CPU The document does not recommend universal gastric cancer screening for the US population. It does not establish definitive surveillance intervals for every combination of risk factors. It does not provide randomized evidence that surveillance reduces mortality across all patient groups. It also does not eliminate the need for clinical judgement. Because this is an expert review based on literature synthesis and expert opinion rather than a formally graded systematic guideline, its principal strength is practical coherence. It gathers the available evidence into a clinically usable pathway for an area where practice has often been variable. Its limitations are equally important. Key unanswered questions include: The optimal interval after a negative index endoscopy The most appropriate surveillance timing for different risk profiles How best to implement risk-based screening across diverse US healthcare systems Whether these strategies reduce gastric cancer incidence Whether they lead to earlier-stage diagnosis Whether they ultimately reduce mortality These are not minor gaps. They are the questions future prospective studies will need to address. Clinical Takeaway The AGA Clinical Practice Update reframes gastric cancer prevention as a targeted, quality-dependent, risk-based process. Patients should enter the pathway because they have meaningful baseline risk—not simply because an upper endoscopy happens to be available. Once they enter, the value of the strategy depends on a careful examination, systematic and anatomically labelled biopsies, clear pathology reporting, appropriate management of H pylori , and thoughtful interpretation of premalignant findings. Not every patient with gastric intestinal metaplasia requires the same surveillance plan. The more useful question is whether the index examination has adequately defined the patient’s risk. This CPU provides clinicians with a sensible framework for answering that question. However, it remains expert-review guidance rather than definitive outcome-proven evidence. It should improve clinical consistency and encourage stronger collaboration between endoscopists and pathologists, while leaving room for shared decision-making wherever the evidence remains uncertain. Five Key Clinical Takeaways This is an expert review, not a randomized trial or formally graded guideline. Its advice should guide clinical reasoning without being interpreted as definitive comparative-effectiveness evidence. Screening is intended for selected higher-risk individuals. It is not a recommendation for universal gastric cancer screening in the general US population. The quality of the index endoscopy matters. Careful inspection, image enhancement, cleansing, photodocumentation, and systematic biopsies are essential for meaningful risk stratification. Surveillance should be based on the complete risk profile. Severity and extent of atrophy or intestinal metaplasia, histologic subtype, dysplasia, H pylori status, family history, and other risk factors should be considered together. Surveillance should stop when treatment is no longer realistic. Detection has value only when the patient is fit enough to benefit from endoscopic or surgical intervention. Source Reference Shah SC, Wang AY, Wallace MB, Hwang JH. AGA Clinical Practice Update on Screening and Surveillance in Individuals at Increased Risk for Gastric Cancer in the United States: Expert Review. Gastroenterology. 2025;168(2):405–416.e1. Published online December 23, 2024. DOI: 10.1053/j.gastro.2024.11.001.

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5 min readAug 3, 202651reads

IBD Biologic Sequencing After Anti-TNF and Vedolizumab Failure: Choosing the Third-Line Agent

A 31-year-old woman with ileocolonic Crohn's disease has lost response to adalimumab after eighteen months, switched to vedolizumab, and now presents at week 30 with a CRP of 42, a calprotectin over 800, and a repeat colonoscopy showing unhealed ulceration. Two mechanisms are gone. The next choice is no longer obvious, and it carries more weight than either of the first two. The core clinical problem Sequencing after a single biologic failure is well-trodden ground — the data on anti-TNF-to-vedolizumab or anti-TNF-to-ustekinumab switches is deep, and most gastroenterologists move through it reflexively. Dual failure is different. Once anti-TNF and vedolizumab have both failed, the remaining evidence base is thinner, drawn mostly from post-hoc trial subgroups and real-world cohorts rather than trials designed around this population. IBD biologic sequencing after anti-TNF and vedolizumab failure has to account for how mechanism of failure — immunogenic loss of response versus primary non-response versus mechanistic exhaustion — changes the odds for whatever comes next, and clinicians who treat this decision the same way they treated the first switch tend to underestimate how much efficacy has already eroded. What the data actually shows about efficacy decay Across pivotal trials for ustekinumab, vedolizumab, and risankizumab, remission rates fall in a fairly consistent stepwise pattern as prior biologic exposure accumulates — patients with zero or one prior failure respond meaningfully better than those with two or more. The upadacitinib U-ENDURE program is the clearest illustration of this in a dual-refractory population specifically: efficacy outcomes were stratified not just by number of prior failures but by which classes had failed (anti-TNF, ustekinumab, vedolizumab/natalizumab), and patients with prior failure of two or more mechanisms still derived clinical benefit from upadacitinib, though at lower absolute rates than biologic-naive patients. That is the central, practice-changing finding for this scenario: a JAK inhibitor doesn't reset the deck, but it does not appear to lose efficacy proportionally to the number of prior mechanisms exhausted, which distinguishes it from what's typically seen when cycling between antibody classes with overlapping resistance patterns. Sequencing decisions get harder still in fistulizing phenotypes — see our post on ustekinumab for fistulising perianal Crohn's disease and what the GETAID trial adds for how mechanism choice changes when perianal disease is in the picture. Per the ACG Clinical Guideline for Crohn's disease, the decision after dual biologic failure should also reconsider whether the original diagnosis, phenotype, and disease location were fully characterized — stricturing or penetrating disease that looks like drug failure is sometimes a surgical problem wearing a pharmacologic mask. Case in point A 44-year-old man with Crohn's ileitis failed infliximab due to antibody formation at month nine, then failed vedolizumab with adequate trough levels and no antibodies after seven months of therapy — a mechanistic non-response rather than an immunogenic one. Repeat imaging confirmed active inflammation without stricture. Given confirmed mechanistic (not pharmacokinetic) failure of both an anti-TNF and an anti-integrin, the team moved to upadacitinib rather than cycling to ustekinumab, reasoning that a genuinely different pathway — JAK-STAT inhibition rather than another surface-receptor-targeted antibody — offered better odds than a third antibody-class agent given how the first two had failed. He achieved clinical response by week 8 and endoscopic improvement at week 26. Choosing between ustekinumab, risankizumab, and JAK inhibition as the third agent The comparison usually comes down to two questions: how much of the original response was pharmacokinetic versus mechanistic, and how much the safety profile matters for this particular patient. Ustekinumab or risankizumab (IL-12/23 or IL-23 blockade): A reasonable next mechanism if trough levels on the prior anti-TNF or vedolizumab were adequate but response still failed — genuine mechanistic failure of the first two pathways doesn't predict failure of a third that hasn't been tried. IL-23-selective agents like risankizumab now have head-to-head data against ustekinumab in this setting and a favorable long-term safety record. Upadacitinib or other JAK inhibitors: Worth prioritizing when the patient has failed multiple antibody-based mechanisms, when extraintestinal manifestations (peripheral arthritis, in particular) are prominent, or when oral dosing matters for adherence. The trade-off is a boxed warning profile that requires a real conversation about cardiovascular and thromboembolic risk, especially in patients over 65 or with existing risk factors. If genuinely useful to the patient in front of you, framing it as pharmacokinetic failure → try a mechanism-appropriate re-challenge or dose optimization, versus mechanistic failure → change class entirely, keeps the decision tractable instead of defaulting to "whatever hasn't been tried yet." A frequently overlooked point The instinct after two failures is to treat the third agent selection as the most important decision in the case, but the more consequential error is skipping therapeutic drug monitoring before making that call. A patient labeled as a vedolizumab failure with subtherapeutic troughs and no antibodies hasn't failed the mechanism — they've failed the dose. It's also worth ruling out a genuinely different driver before cycling to a fourth mechanism: a subset of refractory patients carry anti-IL-10 neutralizing autoantibodies rather than conventional treatment-resistant IBD — a mechanistically distinct, HLA-linked subtype that downstream cytokine blockade won't touch, and one worth testing for before assuming you've simply run out of biologics. Bottom line for clinical practice Confirm mechanistic failure with trough levels and antibody testing before concluding a drug — rather than a dose — has failed. After confirmed dual mechanistic failure, JAK inhibition (upadacitinib) retains meaningful efficacy and doesn't appear to decay proportionally with prior biologic count, per U-ENDURE subgroup data. Reserve a third antibody-class agent (ustekinumab or risankizumab) for cases where the prior two failures were pharmacokinetic, immunogenic, or otherwise mechanism-specific rather than a true ceiling on antibody-based therapy. Re-image or re-scope before assuming pharmacologic failure — stricturing disease masquerading as drug failure is a surgical referral, not a fourth biologic. Discuss cardiovascular and thromboembolic risk explicitly before starting a JAK inhibitor in this population; the discussion belongs in the chart, not just the consent form. Cases like this rarely resolve from a single guideline table — they need the trough levels, the imaging, and the phenotype pulled together in one place before the next agent gets chosen. Walk GastroAGI through a case like this and it will return a reasoned, guideline-anchored response in seconds.

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15 min readJul 31, 202637reads

REFINED-ASUC Criteria: A Modern Approach to Diagnosing Acute Severe Ulcerative Colitis

Patients rarely read the textbook before arriving in hospital. A patient with ulcerative colitis may present with frequent bloody stools, tachycardia, anaemia, low albumin, nocturnal bowel movements, and a rising inflammatory burden—but may already have been taking oral corticosteroids for several days. Another may be receiving an advanced therapy that partially suppresses fever or C-reactive protein without adequately controlling the colitis. Neither patient necessarily presents in the classical manner described by criteria developed more than 70 years ago. This is the problem addressed by the article: “New Diagnostic Criteria for Acute Severe Ulcerative Colitis in the Modern Treatment Era: A Modified Delphi Consensus by REFINED-ASUC.” Published online in Clinical Gastroenterology and Hepatology on July 22, 2026, the paper reports the work of the Refined Evaluation Framework and INvEstigations for Diagnostics in ASUC, known more conveniently as the REFINED-ASUC Working Group. Its DOI is 10.1016/j.cgh.2026.07.011. The study does not compare drugs, rescue therapies, or surgical strategies. It is not a randomized trial, a prospective patient cohort, or a treatment guideline. It is a modified Delphi consensus designed to answer a deceptively difficult question: How should acute severe ulcerative colitis be diagnosed when modern therapy has already altered the patient’s presentation? That question matters because diagnosing acute severe ulcerative colitis, or ASUC, is not simply an exercise in classification. The diagnosis may trigger hospital admission, infection testing, endoscopic assessment, radiologic evaluation, close physiological monitoring, intravenous treatment, early rescue-therapy planning, and surgical consultation. In severe colitis, diagnostic delay is rarely improved by optimism. Why the traditional ASUC definition now feels incomplete The diagnosis of ASUC has traditionally relied on the 1955 Truelove and Witts criteria. These criteria have endured because they are clinically practical and historically important. They helped generations of clinicians recognize a dangerous form of ulcerative colitis that required urgent inpatient management. However, the therapeutic world in which those criteria were developed was very different from modern inflammatory bowel disease practice. Today, a patient may arrive in hospital while already receiving: Oral corticosteroids Biologic therapy Small-molecule treatment Combination treatment Previous rescue therapy Treat-to-target monitoring Treatment may alter the clinical phenotype. Corticosteroids may reduce fever or suppress the C-reactive protein response. Advanced therapies may partially improve bowel frequency without adequately controlling bleeding. A patient may appear less systemically inflamed on paper while still having dangerous mucosal disease. This creates a clinical dilemma. Should a patient be considered less severely ill because one laboratory marker has been partially suppressed by treatment? Or should the threshold for concern change because the patient is already receiving therapy that ought to have improved the disease? REFINED-ASUC addresses this mismatch by incorporating treatment exposure directly into diagnostic reasoning. That is perhaps its most important conceptual contribution. Treatment history is no longer background information. It becomes part of the diagnostic framework. A familiar scenario in modern IBD practice Consider a patient with established ulcerative colitis who has been taking high-dose oral corticosteroids for several days. The patient reports six or seven bowel movements daily, visible blood in roughly one-third of them, nocturnal symptoms, progressive fatigue, and reduced oral intake. The CRP is elevated, but not dramatically so. Under a rigid interpretation of older criteria, the patient may appear not to satisfy every expected marker of systemic severity. Yet something is clearly wrong. The patient is already receiving treatment that should have reduced inflammation. The persistence of bleeding, frequent bowel movements, nocturnal symptoms, and systemic decline may therefore be more concerning—not less. This is where experienced clinical judgment often begins to whisper before the criteria begin to shout. REFINED-ASUC attempts to turn some of that modern clinical reasoning into a more structured diagnostic framework. How the REFINED-ASUC consensus was developed The study used a four-round Delphi process followed by a consensus meeting. The participating experts were gastroenterologists from: Europe North America The Asia-Pacific region Together, they formed the REFINED-ASUC Working Group. Consensus was defined as: At least 70% agreement or disagreement for Likert-scale questions At least 70% homogeneity for single-choice or multiple-choice responses This methodology is appropriate when clinical practice has evolved more quickly than the available validation evidence. A Delphi process allows experts to review statements repeatedly, reconsider their positions, and move toward a defined level of agreement. It is particularly useful when developing diagnostic definitions, research frameworks, or consensus terminology. However, its limitations must be understood. The participants were expert gastroenterologists—not hospitalized patients. There was no patient-level intervention. There was no treatment comparator. The outcomes were consensus statements and proposed diagnostic criteria, not colectomy rates, mortality, steroid response, or long-term remission. A Delphi consensus tells us what knowledgeable experts agreed should be considered. It does not prove that the resulting criteria predict clinical outcomes. Expert agreement is valuable. Nature, unfortunately, is not obliged to agree with the experts until the criteria are tested prospectively. The proposed REFINED-ASUC diagnostic framework For patients already receiving advanced therapy or corticosteroids, the REFINED-ASUC group reached consensus on a structure involving: Three major criteria plus at least two minor criteria. The three major criteria The proposed major criteria are: C-reactive protein at least two times the upper limit of normal At least six bowel movements per 24 hours Visible blood in at least 50% of bowel movements over 24 hours These criteria combine inflammatory burden, stool frequency, and bleeding severity. This matters because no single component adequately captures the clinical syndrome. Frequent bowel movements alone may occur for several reasons. CRP may be affected by treatment or individual biological variation. Bleeding alone does not define the full systemic severity of the illness. Together, however, they describe a patient with active, clinically significant colitis despite ongoing therapy. The minor criteria The proposed minor criteria are: Low albumin Increased heart rate Nocturnal bowel movements Low haemoglobin Increased body temperature Elevated leukocyte count These minor criteria broaden the framework beyond stool counting. They capture nutritional deterioration, inflammatory stress, blood loss, systemic response, and disruption of normal daily physiology. Anyone who has looked after patients with severe ulcerative colitis knows that nocturnal bowel movements carry a particular significance. A bowel that repeatedly wakes the patient during the night is not respecting office hours, and severe inflammation rarely does. Why the major-plus-minor structure is clinically meaningful The proposed framework recognizes that ASUC is not simply “diarrhoea with a high CRP.” It is a severe inflammatory syndrome with multiple dimensions: Stool frequency Visible bleeding Systemic inflammation Anaemia Nutritional compromise Tachycardia Fever Leukocytosis Nocturnal disease activity A major-plus-minor structure may help clinicians identify patients who are seriously unwell even when no single variable appears dramatic in isolation. For example, imagine a patient receiving advanced therapy who has: Six bowel movements daily Visible blood in more than half CRP more than twice the upper limit of normal Low albumin Tachycardia Nocturnal bowel movements The overall pattern is far more informative than any one value. Clinical severity often lives in the combination. The laboratory system may display each abnormality in a separate row. The clinician’s task is to recognize that the abnormalities belong to the same patient. Why visible bleeding remains central One of the three major criteria is visible blood in at least 50% of bowel movements during 24 hours. This is clinically understandable. Visible bleeding supports the presence of ongoing active mucosal inflammation and helps distinguish severe colitis from other causes of frequent bowel movements, including functional symptoms, medication effects, or non-inflammatory diarrhoea. In a severe ulcerative colitis flare, bleeding is not merely an inconvenient symptom. It represents continuing mucosal injury. However, the threshold must be interpreted carefully. The source supports this percentage as a consensus-derived diagnostic component. It does not prove that 49% represents low risk while 50% represents high risk. Biology is rarely impressed by a one-percentage-point administrative boundary. Nor does the consensus establish that the visible bleeding threshold independently predicts colectomy, treatment failure, or mortality. It is a proposed diagnostic marker requiring prospective validation. The threshold should support judgment, not replace it. High-dose corticosteroids require different thinking One of the most intellectually interesting aspects of REFINED-ASUC is its separate consideration of patients already receiving high-dose corticosteroids. For this subgroup, the panel supported lower thresholds: CRP at least one times the upper limit of normal Visible blood in at least 33% of bowel movements over 24 hours Why lower the thresholds? Because high-dose corticosteroids may partly suppress the inflammatory expression of disease. A patient already receiving substantial corticosteroid treatment may not demonstrate the same degree of CRP elevation or bleeding burden as an untreated patient, even when the underlying disease remains severe. Waiting for more dramatic abnormalities may therefore delay recognition. Consider a patient who has already received several days of high-dose corticosteroids but continues to experience frequent stools, one-third visibly bloody, nocturnal symptoms, anaemia, and tachycardia. The persistence of this disease activity despite therapy should increase concern. The patient has not merely arrived with severe symptoms. The patient has failed to improve adequately despite treatment intended to suppress them. REFINED-ASUC therefore makes an important diagnostic adjustment: The meaning of a clinical finding depends partly on what treatment preceded it. This is sensible medicine. A temperature of 37.8°C means one thing in an untreated patient and may mean something different in a patient receiving medication that suppresses inflammation. The same principle applies to CRP and bleeding burden. What about patients who have not received treatment? The panel agreed that similar diagnostic principles might apply to untreated patients. However, formal consensus was not achieved for that group. This is an important boundary. It would be tempting to describe REFINED-ASUC as a universal replacement for existing ASUC criteria. The source does not support that claim. The strongest consensus applies to patients already receiving advanced therapy or corticosteroids, including a separate approach for patients on high-dose corticosteroids. For untreated patients, the experts saw potential relevance but did not reach the required consensus threshold. Clinicians should therefore present REFINED-ASUC as a modern diagnostic proposal with particular relevance to treated patients—not as a fully established definition for every acute severe ulcerative colitis presentation. Endoscopy still matters The REFINED-ASUC panel agreed that endoscopy should confirm the diagnosis and help exclude cytomegalovirus infection. This is an important reminder that clinical and laboratory criteria do not replace direct assessment of the disease process. Severe colitis may coexist with or be complicated by infection. CMV infection can alter management and may be particularly relevant in patients exposed to immunosuppressive therapy. The criteria may help identify suspected ASUC. Endoscopy helps evaluate the mucosa and assess for competing or contributing pathology. For fellows, the teaching point is straightforward: Do not allow a scoring system to become a substitute for looking at the disease when it is clinically appropriate to do so. A checklist can organize thought. It cannot perform the endoscopy. Radiology and the exclusion of toxic megacolon The panel also agreed that radiologic investigations should support exclusion of toxic megacolon. This is essential because severe colitis is not only an inflammatory problem. It can become a structural and systemic emergency. A patient with abdominal distension, systemic toxicity, tenderness, or concerning clinical deterioration requires assessment beyond stool frequency and CRP. No proposed diagnostic framework should create false reassurance when a major complication is developing. REFINED-ASUC therefore remains part of a broader safety pathway that includes: Clinical assessment Laboratory evaluation Endoscopic confirmation CMV exclusion Radiologic assessment Monitoring for complications The diagnosis of ASUC is a synthesis, not a single laboratory result. How clinicians may use REFINED-ASUC in practice The most reasonable clinical use of REFINED-ASUC is as a structured framework for evaluating contemporary patients whose presentation may have been modified by treatment. When assessing possible ASUC, clinicians may now pay closer attention to documenting: Current and recent corticosteroid exposure Advanced therapy exposure Bowel movement frequency over 24 hours Proportion of bowel movements containing visible blood Nocturnal bowel movements CRP relative to the laboratory upper limit of normal Albumin Haemoglobin Heart rate Body temperature Leukocyte count This may improve communication between emergency clinicians, gastroenterologists, IBD nurses, surgeons, and trainees. “Severe flare” can mean different things to different people. A structured record of bowel frequency, bleeding percentage, treatment exposure, and systemic markers provides a more precise clinical language. It may also help identify patients whose disease is more concerning than the CRP alone suggests. A practical admission scenario Imagine two patients presenting with ulcerative colitis symptoms. Patient A Seven bowel movements daily Visible blood in most stools CRP more than twice the upper limit of normal Low albumin Tachycardia Nocturnal symptoms Currently receiving advanced therapy Patient B Six bowel movements daily Visible blood in one-third CRP just above the upper limit of normal Anaemia Nocturnal symptoms Already taking high-dose corticosteroids The first patient fits the proposed major-plus-minor framework relatively clearly. The second may appear less inflammatory if the CRP is considered without context. However, the lower thresholds proposed for high-dose corticosteroid exposure may appropriately raise concern. This is precisely the type of patient for whom the REFINED-ASUC framework may be useful. It encourages clinicians to ask not only: “How abnormal are the findings?” but also: “How abnormal are these findings given the treatment the patient is already receiving?” That is a more sophisticated clinical question. What REFINED-ASUC does not tell us The source does not prove that applying the proposed criteria will: Reduce colectomy Improve survival Shorten hospital stay Predict corticosteroid failure Identify the ideal rescue therapy Prevent complications Improve long-term remission Reduce readmissions The consensus has not yet been prospectively validated against these outcomes. It is also not a treatment guideline. The study does not compare: Intravenous corticosteroids Infliximab Ciclosporin JAK inhibitors Other rescue strategies Surgical timing Colectomy approaches Its focus is diagnosis. Clinicians should also avoid using the criteria to dismiss serious disease when a patient narrowly fails to meet a numerical threshold. A patient does not become safe because one bowel movement contained insufficient blood to satisfy a percentage calculation. Clinical criteria guide recognition. They do not relieve the clinician of responsibility for the patient in front of them. Strengths of the REFINED-ASUC consensus The greatest strength of the consensus is that it directly addresses modern treatment reality. Many patients presenting with severe ulcerative colitis are no longer treatment-naïve. They may already be receiving therapies that alter symptoms and inflammatory markers. REFINED-ASUC recognizes this explicitly. A second strength is the international composition of the expert group, with gastroenterologists from Europe, North America, and the Asia-Pacific region. A third strength is the structured four-round Delphi process and the use of predefined consensus thresholds. A fourth strength is the breadth of the proposed framework. It does not rely on stool frequency alone but includes bleeding, inflammatory markers, nutritional status, haematologic changes, vital signs, nocturnal symptoms, endoscopy, infection assessment, and radiology. The framework therefore reflects how experienced clinicians actually assess severe colitis: by integrating multiple signals. Important limitations The principal limitation is the evidence type. A modified Delphi process provides expert consensus, not diagnostic validation. The proposed criteria have not yet demonstrated: Sensitivity Specificity Predictive value Reproducibility Prognostic accuracy Impact on clinical outcomes The thresholds also require testing across different laboratories, healthcare systems, patient populations, treatment backgrounds, and disease severities. Using CRP relative to the upper limit of normal may improve portability between laboratories, but that does not guarantee equal performance in all settings. The absence of formal consensus for untreated patients is another important limitation. It prevents the framework from being presented as universal. Finally, some clinical variables—such as the exact proportion of bowel movements containing visible blood—may be difficult to measure reliably in routine care. Patients do not always arrive with a perfectly completed 24-hour spreadsheet, and few would consider that a reasonable expectation during an acute severe flare. Implementation will therefore require practical documentation systems. What future research needs to establish The next step is prospective validation. Future studies should test whether the REFINED-ASUC criteria identify patients who experience: Failure of corticosteroid therapy Need for rescue treatment Colectomy Readmission Complications Prolonged hospitalization Diagnostic reclassification after infection testing Researchers should also examine how the criteria perform across different advanced therapies and corticosteroid doses. Patients receiving treatment should not automatically be considered one homogeneous group. Different therapies may alter clinical and laboratory expression in different ways. Implementation studies will also be necessary. Can clinicians reliably record the proportion of bloody bowel movements? Can nocturnal symptoms be documented consistently? Can electronic admission templates improve data capture? Can the criteria be applied similarly by IBD specialists, general gastroenterologists, emergency physicians, and trainees? A diagnostic framework is only useful when clinicians can apply it accurately at the bedside. Clinical Takeaway The REFINED-ASUC criteria address a genuine problem in modern inflammatory bowel disease care: diagnosing acute severe ulcerative colitis in patients whose clinical presentation may already have been modified by corticosteroids or advanced therapy. For treated patients, the consensus proposes a framework based on three major criteria plus at least two minor criteria. The major criteria are: CRP at least twice the upper limit of normal At least six bowel movements per 24 hours Visible blood in at least 50% of bowel movements The minor criteria include: Low albumin Increased heart rate Nocturnal bowel movements Low haemoglobin Increased temperature Elevated leukocyte count For patients receiving high-dose corticosteroids, lower thresholds were proposed for CRP and visible bleeding. The framework also reinforces the role of endoscopy in confirming disease and excluding CMV infection, together with radiologic assessment for toxic megacolon. The most balanced interpretation is that REFINED-ASUC provides a thoughtful, contemporary diagnostic proposal—not a validated outcome-prediction tool and not a treatment guideline. For clinicians, its greatest value may be intellectual as much as numerical: Disease severity should be interpreted in the context of the treatment the patient has already received. After 25 years in gastroenterology, that principle feels less like a new rule and more like good clinical sense finally being given a formal structure. Five Key Clinical Takeaways REFINED-ASUC is a modified Delphi consensus, not a randomized trial, patient cohort, or treatment guideline. It addresses a modern diagnostic gap by incorporating corticosteroid and advanced therapy exposure into ASUC assessment. For treated patients, the proposed framework uses three major criteria plus at least two minor criteria. Patients receiving high-dose corticosteroids are considered separately, with lower proposed CRP and visible bleeding thresholds. Prospective validation is required before REFINED-ASUC can be considered an established predictor of treatment failure, colectomy, or other clinical outcomes. Source Reference Raine T, Peyrin-Biroulet L, Begun J, Biedermann L, Blumenstein I, Cheifetz AS, Colombel JF, Dulai PS, Gecse KB, Jairath V, Nakase H, Panaccione R, Reinisch W, Verstockt B, Higgins PDR. New Diagnostic Criteria for Acute Severe Ulcerative Colitis in the Modern Treatment Era: A Modified Delphi Consensus by REFINED-ASUC. Clinical Gastroenterology and Hepatology. Published online July 22, 2026. DOI: 10.1016/j.cgh.2026.07.011.

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6 min readJul 31, 202625reads

Smoking Cessation in Crohn's Disease: Why E-Cigarettes Belong in the Conversation

A 28-year-old woman with ileal Crohn's disease, two prior resections, and a pack-a-day habit tells you she's tried patches twice and lasted eleven days both times. She's not opposed to quitting. She's opposed to failing again. The conversation that follows determines whether she becomes one of the roughly 1 in 8 smokers with Crohn's disease who actually quit - or one of the majority who don't. Smoking is the single most consistently reproduced modifiable risk factor for a worse disease course in Crohn's disease, and gastroenterologists have known this for decades. What's changed is the toolkit. A 2026 JAMA Special Communication from the Treatment Research Network of the Society for Research on Nicotine and Tobacco now recommends that clinicians integrate nicotine e-cigarettes into shared decision-making conversations about smoking cessation in Crohn's disease, alongside FDA-approved pharmacotherapy - not instead of it. For a GI-specific population where relapse risk, not just cardiovascular or oncologic risk, hangs on quitting, this changes what "standard counseling" should look like at the point of care. The Clinical Problem: Counseling That Doesn't Match the Stakes Gastroenterologists already tell Crohn's disease patients to quit smoking. What most don't do is engage with why quit attempts fail, or offer a method beyond a pamphlet and a referral. The result is a gap between what we know about smoking cessation in Crohn's disease and what we actually do at the bedside. Nicotine replacement therapy has modest real-world quit rates, varenicline carries tolerability concerns some patients won't accept, and many patients arrive having already failed both. Meanwhile, nicotine e-cigarettes are misunderstood by clinicians almost as often as by patients - a persistent overestimation of relative harm that the JAMA authors argue is now out of step with the evidence. For a GI clinic seeing a patient with active or recent flares, this isn't an abstract public health issue. It's a modifiable variable sitting in the room. First Major Section: What Quitting Actually Buys a Crohn's Disease Patient The magnitude of benefit is the part worth stating plainly, because it's larger than most non-GI clinicians assume. In Cosnes and colleagues' intervention study, Crohn's disease patients who quit smoking for more than a year had a flare-up risk roughly two-thirds lower than those who continued, and their disease course converged with that of patients who had never smoked at all. Later work in the biologic era reproduced the same directional effect: continuing smokers had higher rates of corticosteroid use and intestinal resection, while quitters tracked with nonsmokers. This is not a modest risk reduction of the kind gastroenterologists are used to discounting. It rivals, and in some cohorts exceeds, the benefit of adding a biologic. The mechanism is still incompletely defined - proposed pathways include effects on mucosal microvascular perfusion, mucus composition, and innate immune signaling - but the clinical signal has been consistent since the 1990s. What has lagged is translating that signal into a structured cessation strategy embedded in routine Crohn's disease management, rather than a single line in the after-visit summary. Case in Point A 34-year-old man with stricturing ileocolonic Crohn's disease, on adalimumab, presents with his third flare in 18 months despite objective biologic drug levels in range and no evidence of antibody formation. He smokes 10–15 cigarettes daily, has tried nicotine gum twice, and describes the cravings as "worse than the disease some days." Rather than escalating therapy again, his gastroenterologist reframes the visit around smoking as an independent driver of his relapse pattern, separate from drug failure. The clinician walks through the relative-risk data directly - including that a nicotine e-cigarette is a reasonable option to raise alongside patch and gum, given his prior failures with both. The patient opts to try a nicotine e-cigarette under a structured taper plan with follow-up at four weeks. At three months, he's cigarette-free, still using the e-cigarette at a reduced nicotine concentration, and his biologic has been left unchanged rather than escalated to a second agent. Second Major Section: Building E-Cigarettes Into the Conversation Without Overselling Them The JAMA Special Communication's central recommendation is narrower than "recommend e-cigarettes" - it's to integrate them into a shared decision-making conversation that also covers NRT, varenicline, and bupropion, so the patient chooses with accurate information about relative risk rather than by default. For Crohn's disease patients specifically, that conversation should include three things most cessation scripts skip: the magnitude of GI-specific benefit from quitting, the fact that e-cigarettes deliver nicotine (still not risk-free, still relevant to a mucosal disease) without combustion products, and a plan for tapering off the e-cigarette itself rather than treating it as a permanent substitute. Two practical paths tend to work in a GI clinic that doesn't run its own tobacco program: refer to a structured cessation service and remain in the loop on whether e-cigarettes were part of that conversation, or manage the discussion directly and document a specific plan - product type, nicotine concentration, and a re-evaluation date - rather than a general instruction to quit. Patients who've already failed NRT twice are disproportionately the ones who benefit from having a different option named explicitly, rather than being sent back to the same failed method a third time. A Frequently Overlooked Point The instinct many gastroenterologists have is to treat smoking cessation as someone else's job - primary care's, pulmonology's, a quitline's - because IBD management already consumes the visit. But the relapse-risk data means that in a Crohn's disease patient who smokes, cessation counseling isn't adjacent to disease management; it functions as disease management, with an effect size comparable to therapy escalation. Deferring it to a specialty better equipped to run structured tobacco programs is reasonable. Deferring it indefinitely, or treating it as a single throwaway line at the end of a visit focused on drug levels and imaging, means missing the highest-yield intervention available for a meaningful subset of patients. Bottom Line for Clinical Practice Quote the Cosnes-era finding directly to patients: sustained smoking cessation cuts Crohn's disease flare risk by roughly two-thirds and brings the disease course in line with never-smokers. Before escalating biologic therapy for recurrent flares in a smoker, confirm whether a genuine cessation attempt, with a specific method and follow-up plan, has actually occurred. Offer nicotine e-cigarettes as one option within a shared decision-making conversation for patients who have already failed NRT or varenicline - not as a first-line default. Document product type, nicotine strength, and a taper timeline when e-cigarettes are chosen, and set a re-evaluation date rather than leaving the plan open-ended. Recognize that counseling quality, not counseling existence, predicts quit rates; a generic instruction to stop smoking performs far worse than a structured plan with a named method. Working through a Crohn's disease patient's relapse pattern and wondering how much of it is smoking-driven versus treatment failure? Walk GastroAGI through the case details - it will return a reasoned, guideline-anchored response in seconds.

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14 min readJul 30, 202623reads

Positive FIT Follow-Up: Why Completing Colonoscopy May Matter More Than Timing Alone

We count how many patients were invited for screening, how many returned a faecal immunochemical test, how many tests were positive, and how quickly colonoscopy appointments were offered. The more uncomfortable question is whether the patient actually reached the end of the pathway. A positive faecal immunochemical test, or positive FIT, is not a diagnosis. It does not confirm colorectal cancer, and it does not exclude it. It is a clinically important signal indicating that further evaluation—usually colonoscopy—is required. Yet discussions about positive FIT follow-up often become dominated by one question: How quickly should colonoscopy be performed? One month? Three months? Six months? Timing undoubtedly matters. However, the July 2026 Gut article, “Colonoscopy compliance matters more than time to colonoscopy after a positive FIT result,” asks clinicians and screening programmes to consider an even more fundamental issue: What is the value of rapid colonoscopy targets if a meaningful proportion of patients never undergo colonoscopy at all? The article was published online on July 24, 2026, by Adrien Grancher, Bernard Denis, and Lydia Guittet in Gut . Its DOI is 10.1136/gutjnl-2026-339212, and its PMID is 42498623. It should be read as a clinically important interpretive article rather than a new randomized trial. Its argument builds on an earlier French nationwide retrospective cohort study examining the relationship between time to colonoscopy after positive FIT and the detection of colorectal cancer, advanced-stage colorectal cancer, and advanced adenoma. The central message is not that timing is irrelevant. It is that colonoscopy completion is indispensable. A delayed colonoscopy remains an unfinished task. A colonoscopy that never happens is a failed diagnostic pathway. A positive FIT is a question, not an answer Patients sometimes understandably interpret a positive FIT as meaning that cancer has already been found. Others move in the opposite direction. Because they feel well, they assume the result cannot be particularly important. Neither interpretation is accurate. FIT detects faecal haemoglobin. It identifies people who need further investigation, but it cannot determine the underlying cause by itself. Colonoscopy is the step that allows clinicians to investigate for colorectal cancer and advanced precursor lesions. A positive FIT without subsequent diagnostic evaluation is therefore not completed screening. It is an unresolved clinical question. Consider an illustrative scenario. A 62-year-old patient receives a positive FIT result through an organised screening programme. The result is communicated, a referral is generated, and an appointment is offered. The patient postpones because of work commitments. The second appointment is missed because the bowel preparation instructions seemed confusing. A third letter is sent, but no direct contact occurs. From an administrative perspective, several actions have taken place. From a clinical perspective, almost nothing has been resolved. The test was completed. The pathway was not. This distinction lies at the heart of the July 2026 Gut article. Timing and compliance measure different failures Time to colonoscopy describes the interval between a positive FIT and colonoscopy among patients who undergo the procedure. Colonoscopy compliance describes whether the colonoscopy happens at all. These measures are related, but they are not interchangeable. A screening programme may report an impressive median waiting time while still losing a substantial number of FIT-positive patients before diagnostic completion. Conversely, another programme may have longer waiting intervals but successfully bring a larger proportion of patients to colonoscopy. The first programme looks efficient on a timing dashboard. The second may achieve more diagnostic closure. Medicine occasionally produces situations in which the prettier spreadsheet is not the safer service. The July 2026 article notes a colonoscopy compliance rate of 80% among individuals with a positive FIT in the context under discussion. That means a meaningful proportion of patients did not complete the expected diagnostic step. Every one of those patients remained at unresolved risk. This is why a positive FIT should not disappear into a referral queue after the result has been communicated. The clinically meaningful endpoint is not that a colonoscopy was recommended or booked. It is that the diagnostic evaluation was completed—or that a documented, clinically appropriate alternative decision was made. What the French nationwide cohort investigated The interpretive article builds on a French nationwide retrospective cohort study titled: “Does a long time to colonoscopy after a positive faecal immunochemical test result have a deleterious impact on colorectal cancer outcomes? A nationwide cohort study.” The cohort included individuals with a positive FIT between 2016 and 2019 who subsequently underwent colonoscopy within 24 months. The exposure of interest was the interval from positive FIT to colonoscopy. The evaluated outcomes were: Colorectal cancer Advanced-stage colorectal cancer Advanced adenoma The study also examined individual and socio-geographic characteristics. The population was substantial. A total of 374,113 FIT-positive individuals underwent post-FIT colonoscopy, corresponding to an 86.6% compliance rate in the underlying cohort report. Among those individuals, investigators diagnosed: 21,616 colorectal cancers 122,359 advanced adenomas The scale of the study gives it important descriptive value within an organised national screening setting. However, the study was retrospective. It did not randomly assign patients to early or delayed colonoscopy. It also focused on individuals who ultimately underwent colonoscopy within 24 months. Those details are essential when interpreting the results. What the study found about colonoscopy timing Compared with colonoscopy performed within the 2–3 month interval, the study found no increased observed risk of colorectal cancer, advanced-stage colorectal cancer, or advanced adenoma among those undergoing colonoscopy after three months and up to 24 months. At 12 months, the adjusted odds ratios were: 0.93 for colorectal cancer 1.04 for advanced-stage colorectal cancer 0.88 for advanced adenoma At first glance, this may appear to suggest that timing does not matter. That would be an overinterpretation. The more accurate conclusion is narrower: Among FIT-positive individuals who eventually underwent colonoscopy within 24 months, longer intervals were not associated with a higher observed likelihood of colorectal cancer, advanced-stage colorectal cancer, or advanced adenoma compared with the 2–3 month interval. The study found no association within that population and setting. It did not prove that delaying colonoscopy is harmless for every patient. Those are not equivalent statements. Observational studies can describe patterns and associations. They cannot fully remove the possibility of confounding, selection bias, or systematic differences between patients scoped earlier and those scoped later. For example, clinicians may have prioritised patients with symptoms, higher faecal haemoglobin levels, significant anaemia, concerning medical history, or other risk features. Patients undergoing later colonoscopy may therefore differ from those undergoing earlier procedures in ways not fully reflected by the available data. The absence of a detected association should not be turned into permission for indefinite delay. Completion may matter more than shaving weeks from the waiting time The practical insight from the article is not that screening programmes should become relaxed about waiting periods. It is that programmes should distinguish between two different problems: A patient undergoes colonoscopy later than the preferred interval. A patient never undergoes colonoscopy. Both deserve attention, but the second represents complete loss of diagnostic follow-up. Imagine two screening services. In Service A, most patients receive a colonoscopy within six weeks, but one in five FIT-positive individuals never completes the procedure. In Service B, the average waiting time is somewhat longer, but almost every FIT-positive patient reaches diagnostic colonoscopy. This simplified scenario does not establish which service is better overall. Other factors—including cancer stage, procedure quality, patient risk, and capacity—would also matter. But it illustrates the article’s central argument: an excellent waiting-time target cannot compensate for patients disappearing from the pathway. Reducing an already scheduled patient’s wait by two weeks may be valuable. Finding the patient who was never successfully scheduled may be more valuable still. Faecal haemoglobin may help identify who needs greater urgency One of the most clinically useful findings from the underlying study concerns faecal haemoglobin concentration, often written as f-Hb. Patients with f-Hb concentrations of at least 200 µg/g were: Eight times more likely to have colorectal cancer Eleven times more likely to have advanced-stage colorectal cancer Twice as likely to have an advanced adenoma These comparisons were made against the 30–40 µg/g category. This finding reinforces a point that experienced clinicians already recognise conceptually: not every positive test carries identical risk. “Positive” is a threshold category. The quantitative result may contain additional clinical information. A patient with a markedly elevated f-Hb concentration may require greater urgency than someone with a lower-positive result, particularly when colonoscopy capacity is limited. This does not mean that lower-positive patients can safely be ignored. Every positive FIT still requires appropriate diagnostic follow-up. Instead, quantitative f-Hb may help screening programmes decide who should move closer to the front of the queue without allowing those further back to fall out of the queue altogether. The authors’ conclusion reflects this balance: colonoscopy completion may deserve priority over rigid interval adherence, while higher faecal haemoglobin concentrations support earlier colonoscopy. The mature interpretation is therefore: Completion is fundamental, but urgency should still respond to risk. A booked colonoscopy is not a completed colonoscopy Healthcare systems often treat scheduling as evidence of progress. Clinically, however, an appointment date is only a promise. It does not diagnose colorectal cancer, remove an advanced adenoma, or explain a positive FIT result. Patients may fail to complete colonoscopy for many reasons: Fear of the procedure Anxiety about a possible cancer diagnosis Difficulty understanding bowel preparation Transport limitations Work or caregiving responsibilities Financial concerns Medical comorbidity Poor communication Referral delays Fragmented responsibility between services Previous unpleasant procedural experiences Some patients do not actively refuse colonoscopy. They simply become lost between a positive test, a referral, an appointment letter, and a complex healthcare system. This is why active tracking matters. A screening programme should ideally know whether each FIT-positive patient: Completed colonoscopy Declined after informed discussion Was medically unsuitable Chose an alternative pathway Remains awaiting the procedure Was lost to follow-up The phrase “colonoscopy advised” is not diagnostic closure. Nor, unfortunately, is “patient did not attend” a complete clinical strategy. What clinicians can do differently The article’s message has practical implications for gastroenterologists, primary care clinicians, endoscopy services, and screening-programme leaders. Track patients until the pathway is resolved A positive FIT should trigger follow-up that continues until colonoscopy is completed or another documented clinical decision is reached. Responsibility should not become ambiguous after referral. When everyone assumes someone else is following the patient, the patient may discover that nobody is. Identify barriers before the appointment Patients may miss colonoscopy because they do not understand why it is required, fear the preparation, cannot arrange transport, or believe absence of symptoms means absence of risk. A short, clear conversation can reveal barriers that an automated letter will not. For example: “You have a positive screening test. This does not mean you have cancer, but it does mean we need colonoscopy to understand why the test was positive.” That explanation is simple, accurate, and often more useful than several paragraphs of institutional language. Use risk information intelligently Quantitative f-Hb may help prioritise patients when demand exceeds immediate colonoscopy capacity. Higher-risk patients may need faster access, but the system must still protect lower-priority patients from non-completion. Risk stratification should organise follow-up, not justify abandonment. Measure completion as a quality outcome Time-to-colonoscopy remains important, but screening programmes should also report: Colonoscopy completion rate Reasons for non-completion Time from positive FIT to diagnostic resolution Missed appointment recovery Variation across geographic or socioeconomic groups Completion according to f-Hb category Cancer and advanced adenoma detection A service cannot improve a failure it does not measure. Why this matters when colonoscopy capacity is limited Many screening systems operate under capacity pressure. There may be more positive FIT results than immediately available colonoscopy slots. Endoscopy lists may already contain symptomatic referrals, surveillance procedures, therapeutic cases, urgent bleeding, and patients requiring complex support. The response to limited capacity cannot be to pretend every patient can be scoped instantly. Nor should the response be to accept prolonged waits without scrutiny. The article supports a more intelligent use of resources. Programmes should aim to: Complete colonoscopy for all eligible FIT-positive patients Prioritise those at higher risk Prevent missed appointments from becoming permanent loss to follow-up Simplify referral and scheduling Improve bowel-preparation support Communicate the significance of positive FIT clearly Monitor both waiting time and completion There is little value in creating an exceptionally fast pathway for patients who are already engaged while failing to recover those who have quietly fallen out of the system. Efficiency is not only about moving quickly. It is also about making sure the right patients arrive. What this evidence should not be used to claim The study should not be presented as evidence that colonoscopy can safely be postponed for up to 24 months in every FIT-positive individual. It should not be used to reassure patients that delay carries no risk. It should not be interpreted as a recommendation to weaken existing national or local screening guidance. It should not be described as proving that early and late colonoscopy are clinically equivalent. The underlying evidence was observational, not randomized. The study population consisted of patients who ultimately underwent colonoscopy within 24 months. Differences between earlier and later groups may have influenced the observed findings. The article’s title is deliberately provocative, but its message is not an invitation to complacency. It is a reminder to focus on the entire pathway. “Compliance matters more” does not mean “time does not matter.” It means that discussing optimal timing becomes rather theoretical when the colonoscopy never occurs. Strengths of the evidence The underlying cohort has several important strengths. First, it was large, including more than 374,000 FIT-positive individuals who underwent colonoscopy. Second, it was embedded within a national screening context, giving it relevance for programme-level planning. Third, it examined meaningful clinical outcomes rather than waiting times alone: Colorectal cancer Advanced-stage colorectal cancer Advanced adenoma Fourth, it incorporated quantitative faecal haemoglobin, providing clinically useful information for risk stratification. Finally, the July 2026 Gut article draws attention to a quality measure that can be overshadowed by timing targets: whether diagnostic colonoscopy was completed. Important limitations The most important limitation is the retrospective observational design. Time to colonoscopy was not assigned randomly. Earlier and later groups may have differed in symptoms, clinical urgency, f-Hb concentration, geography, healthcare access, comorbidity, or other factors. The cohort also included individuals who completed colonoscopy within 24 months. Patients who never underwent colonoscopy are central to the compliance question, but their colonoscopy-detected outcomes cannot be evaluated in the same manner. The findings arose from a particular French national screening setting. Other countries may use different FIT thresholds, referral systems, colonoscopy capacity, navigation processes, and reporting standards. The July 2026 article is also not a guideline. It can inform clinical thinking and quality improvement, but it should not replace national screening recommendations or local policy. What future research should examine Future research should move beyond describing non-completion and test interventions designed to prevent it. Relevant strategies may include: Patient-navigation programmes Direct colonoscopy scheduling Reminder systems Primary care follow-up Simplified referral pathways Bowel-preparation education Transport support Multilingual communication Outreach after missed appointments Risk-based triage using quantitative f-Hb Research should also examine whether prioritisation based on faecal haemoglobin improves outcomes without creating inequity. A risk-based system may be clinically sensible, but it must not create a lower-priority group that becomes an invisible group. Future studies should report both time to colonoscopy and colonoscopy completion. One without the other provides an incomplete picture. Timing tells us how quickly the system moved. Completion tells us whether the system arrived. Clinical Takeaway The July 2026 Gut article “Colonoscopy compliance matters more than time to colonoscopy after a positive FIT result” highlights a fundamental principle of colorectal cancer screening: A positive FIT only creates benefit when the diagnostic pathway is completed. The underlying French nationwide retrospective cohort included 374,113 FIT-positive individuals who underwent colonoscopy within 24 months. Longer intervals beyond three months were not associated with a higher observed risk of colorectal cancer, advanced-stage colorectal cancer, or advanced adenoma compared with colonoscopy at 2–3 months. However, this finding does not prove that delay is harmless, nor does it support postponing colonoscopy intentionally. Higher faecal haemoglobin concentrations identified patients with substantially greater likelihood of colorectal cancer, advanced-stage disease, and advanced adenoma, supporting risk-based prioritisation when resources are constrained. The most balanced clinical interpretation is straightforward: Positive FIT follow-up should be timely, but above all, it must be completed. For screening programmes, the meaningful endpoint is not a test result, a referral letter, or an appointment date. It is diagnostic resolution. Five Key Clinical Takeaways The July 2026 Gut article argues that completing colonoscopy after positive FIT may be more important than focusing exclusively on rigid timing targets. The underlying French nationwide retrospective cohort included 374,113 FIT-positive individuals who underwent colonoscopy within 24 months. Longer intervals up to 24 months were not associated with a higher observed risk of colorectal cancer, advanced-stage colorectal cancer, or advanced adenoma compared with the 2–3 month interval. An f-Hb concentration of at least 200 µg/g was associated with substantially higher likelihood of colorectal cancer, advanced-stage colorectal cancer, and advanced adenoma compared with the 30–40 µg/g category. The evidence supports stronger tracking, navigation, risk-based prioritisation, and colonoscopy-completion systems—not deliberate delay or departure from established screening guidance. Source Reference Grancher A, Denis B, Guittet L. Colonoscopy compliance matters more than time to colonoscopy after a positive FIT result. Gut. Published online July 24, 2026. DOI: 10.1136/gutjnl-2026-339212. PMID: 42498623. Related underlying cohort: Grancher A, Denis B, Plaine J, Vidal-Sengchanh S, Quertier M-C, Quintin C, Guittet L. Does a long time to colonoscopy after a positive faecal immunochemical test result have a deleterious impact on colorectal cancer outcomes? A nationwide cohort study. Gut.

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14 min readJul 30, 202658reads

2026 ESGE–ESGENA Sedation Guideline for GI Endoscopy: Practical Lessons for Safer Clinical Practice

After 25 years in gastroenterology, I have learned that the word routine deserves cautious handling. A routine colonoscopy may suddenly become technically difficult. A routine upper gastrointestinal endoscopy may encounter an unexpected bleeding lesion. A patient who looked perfectly comfortable in the assessment area may become hypoxic shortly after sedation begins. Sedation itself is often described as routine. In practice, it is anything but trivial. When sedation works well, almost nobody notices it. The patient is comfortable, the endoscopist can concentrate, the nursing team remains calm, and recovery proceeds without incident. When sedation is poorly planned, however, it can dominate the entire procedure. The newly published “Sedation for gastrointestinal endoscopy: ESGE and ESGENA Guideline” places this familiar but safety-critical part of endoscopy back where it belongs: at the centre of procedural planning. The guideline was published online on July 21, 2026 , in Endoscopy by the European Society of Gastrointestinal Endoscopy (ESGE) and the European Society of Gastroenterology and Endoscopy Nurses and Associates (ESGENA) . Its DOI is 10.1055/a-2898-6540 . This is a professional society guideline rather than a clinical trial. There is no randomized treatment arm, comparator group, predefined patient population, or single outcome measure. Instead, the document is intended to guide the safe organization and delivery of sedation across gastrointestinal endoscopy services. That distinction matters. Guidelines rarely provide the dramatic headline of a positive randomized trial. Their value is quieter but often broader: they help clinicians examine whether everyday practice is as safe, consistent, and defensible as it should be. The sedative is only one part of sedation safety When discussing endoscopy sedation, conversations frequently begin with the drug. Which agent should be used? How much should be given? Who should administer it? These are important questions, but they are not the whole story. Sedation safety begins before the medication is drawn up and continues long after the endoscope has been removed. It includes: Pre-procedure risk assessment Patient selection Informed consent Procedure-specific planning Appropriate staffing Physiological monitoring Airway preparedness Recognition of deterioration Recovery supervision Discharge assessment Documentation Post-procedure instructions In other words, sedation is not a syringe. It is a clinical pathway. Consider two patients scheduled on the same list. The first is a healthy 42-year-old undergoing diagnostic gastroscopy for dyspepsia. The second is a frail 79-year-old with cardiopulmonary disease, possible obstructive sleep apnea, and a prolonged therapeutic procedure planned. Both are attending for gastrointestinal endoscopy. That does not mean they have the same sedation needs. A safe service does not ask only, “What sedation do we normally give for this procedure?” It asks, “What level of sedation risk does this particular patient bring to this particular procedure in this particular setting?” The repetition is intentional. Sedation decisions should be individualized, not inherited from habit. Why a new endoscopy sedation guideline matters in 2026 Modern endoscopy is not the same service it was two decades ago. Diagnostic procedures remain central, but the field has become increasingly interventional. Endoscopic resection, advanced pancreatobiliary procedures, EUS-guided interventions, bariatric endoscopy, foreign body removal, emergency haemostasis, and complex therapeutic procedures may require longer procedure times, greater patient immobility, and more controlled operating conditions. At the same time, the patients arriving in endoscopy units are often older and medically more complex. The endoscopist may therefore face a familiar clinical tension: the procedure requires stable conditions, but deeper or prolonged sedation may increase risk in precisely the patient who most needs the procedure. This is why sedation cannot be reduced to a standard medication protocol attached to a procedure name. A planned ERCP in a medically fit patient, an urgent endoscopy for gastrointestinal bleeding, and an advanced resection in a frail individual may all involve different considerations. The appropriate approach depends on the patient’s condition, procedure complexity, anticipated duration, team competence, monitoring capacity, and availability of additional support. The 2026 ESGE–ESGENA sedation guideline is timely because it encourages clinicians and endoscopy units to review sedation as part of endoscopy-service quality, not merely patient comfort. Comfort matters greatly. But comfort without safety is not a successful sedation strategy. A guideline about teamwork, not professional territory One of the most meaningful features of the guideline is the collaboration between ESGE and ESGENA. Sedation is delivered within a team. The endoscopist may lead the procedure, but safe sedation also depends on the vigilance, training, communication, and judgment of nursing staff, recovery personnel, anesthesia colleagues, and the wider endoscopy service. Anyone who has worked in a busy endoscopy unit knows that deterioration is not always announced dramatically. It may begin with a subtle change in respiratory pattern, a declining oxygen saturation, altered responsiveness, or simply an experienced nurse saying, “This patient does not look quite right.” That sentence has prevented more trouble than many sophisticated devices. The involvement of ESGENA reinforces an important truth: nursing observation, monitoring, documentation, recovery assessment, and escalation are not secondary functions. They are central components of sedation safety. The guideline should therefore not be interpreted as a debate about which professional group “owns” sedation. Patients are rarely impressed by territorial arguments. They expect the entire team to recognize risk, communicate clearly, and respond appropriately. The more useful question is whether the chosen sedation model matches: Patient risk Procedure complexity Staff training Monitoring resources Rescue capability Local regulations Access to anesthesia support From comfort medication to procedural risk management For many clinicians, the most valuable shift may be conceptual. Sedation is often framed primarily as a way to improve comfort and tolerance. That is correct, but incomplete. Sedation is also a form of procedural risk management . The sedation plan can affect whether the procedure can be completed, whether the patient remains physiologically stable, whether the endoscopist can work safely, and whether the team can respond rapidly if complications occur. Imagine a technically demanding endoscopic procedure expected to last considerably longer than routine diagnostic endoscopy. The patient becomes restless, sedation is repeatedly increased, monitoring becomes more difficult, and the team gradually moves from a planned strategy to reactive medication administration. This is a common type of scenario—not because the team lacks skill, but because the sedation requirements may not have been fully anticipated. Good sedation planning attempts to solve that problem before it develops. The correct question is not simply whether the patient can tolerate the first five minutes of the procedure. It is whether the planned sedation model remains appropriate throughout the expected duration and complexity of the intervention. That requires foresight, not merely familiarity with sedative drugs. Pre-procedure assessment should change the plan when necessary A pre-endoscopy assessment becomes meaningful only when its findings are capable of changing management. Recording age, comorbidities, medication exposure, cardiopulmonary status, frailty, aspiration risk, and possible obstructive sleep apnea has limited value if every patient then receives the same pathway. The purpose of assessment is risk recognition. For example, suppose a patient is listed for an apparently straightforward procedure but has significant respiratory disease, reduced physiological reserve, and features suggesting sleep-disordered breathing. The correct response is not necessarily to cancel the procedure or automatically request anesthesia involvement. Nor is it to ignore the findings because “we use this sedation every day.” The findings should trigger a structured decision: Is the planned level of sedation appropriate? Is the setting adequately equipped? Is enhanced monitoring required? Is additional support advisable? Should the procedure be modified or rescheduled? Is the anticipated benefit sufficient to justify the sedation risk? Guidelines are most useful when they improve these decisions before the patient enters the procedure room. Different procedures create different sedation demands A diagnostic upper GI endoscopy, screening colonoscopy, therapeutic ERCP, EUS-guided intervention, endoscopic resection, bariatric procedure, foreign body retrieval, or emergency haemostasis should not automatically be approached as variations of the same sedation problem. Procedure complexity matters. Expected duration matters. Patient positioning matters. The likelihood of discomfort, immobility requirements, aspiration concerns, and the potential need for urgent intervention all matter. In practice, procedure lists often encourage standardization because standardization improves efficiency. But safe standardization should create reliable pathways, not erase clinically important differences. There is a difference between a protocol and an autopilot. A good protocol ensures that the same relevant questions are asked for every patient. Autopilot assumes the answers will always be the same. Monitoring is not simply a documentation exercise Monitoring sometimes becomes so familiar that it risks being treated as a collection of numbers that must appear in the record. That is not its purpose. The purpose of monitoring is to identify physiological change early enough for the team to act before deterioration becomes difficult to reverse. A monitor displaying reassuring values does not replace direct clinical observation. Equally, clinical observation alone may not detect every developing problem promptly. Safe sedation depends on integrating both. The exact monitoring requirements, thresholds, and procedure-specific recommendations should be taken from the complete guideline and interpreted according to local practice and regulations. However, the broader principle is clear: monitoring must be appropriate to the patient, the planned sedation depth, and the procedure being performed. It should also be accompanied by a predefined response. Detecting deterioration without having trained staff, airway equipment, escalation protocols, or rescue capability is similar to installing a smoke alarm without considering how people will leave the building. The alarm is helpful. The response system is what saves the situation. Recovery is still part of the procedure Endoscopists naturally focus on the period during which the endoscope is inside the patient. Sedation does not respect that boundary. A procedure may be technically complete while the patient remains under the physiological effects of sedation. Recovery assessment therefore deserves the same seriousness as pre-procedure assessment and intraprocedural monitoring. Patients must be observed appropriately, assessed against defined discharge criteria, and given clear instructions. A patient opening their eyes and asking for tea is encouraging. It is not, by itself, a validated discharge strategy. Endoscopy units should have consistent recovery and discharge processes rather than relying solely on informal impressions. The patient’s level of alertness, physiological stability, mobility where relevant, supervision arrangements, and understanding of post-procedure advice may all affect safe discharge. Again, the detailed criteria should be taken from the complete guideline and local policy. The broader message is that the sedation pathway ends only when recovery has been assessed properly and responsibility has been transferred safely. What experienced clinicians should reconsider Experience is invaluable in endoscopy, but it carries one occupational hazard: familiar practice can begin to feel equivalent to best practice. They are not always the same. A clinician may have administered sedation in a particular way for many years without encountering a major event. That experience is reassuring, but it does not remove the need to review current guidance. Absence of a previous complication does not prove that the system is optimally designed. It may reflect good practice, fortunate patient selection, skilled staff, or simply the rarity of serious events. The mature clinical approach is not to reject guidelines because experience exists. Nor is it to abandon judgment in favour of rigid rules. The better approach is to place experience in conversation with current guidance. Guidelines show what contemporary evidence and expert consensus suggest. Experienced clinicians understand how recommendations behave in real units, with real staffing limitations, real patients, and the occasional endoscopy list that appears to have been organized by someone with a personal objection to lunch. Both perspectives are needed. What fellows and trainees should learn from the guideline Trainees understandably focus on scope handling, lesion recognition, cannulation, biopsy technique, polypectomy, haemostasis, and resection skills. Sedation can appear to sit in the background—until it suddenly becomes the main clinical problem in the room. A well-trained endoscopist should understand not only how to perform the procedure but also when the proposed sedation plan is unsuitable. This includes recognizing: High-risk patients Procedures likely to be prolonged Situations requiring additional support Early signs of sedation-related deterioration When the procedure should be paused When escalation is necessary When patient safety should take priority over procedural completion There is no technical prize for completing an endoscopy that should have been stopped. Judgment includes knowing when not to proceed, when to modify the plan, and when to ask for help. The ESGE guideline list also includes an earlier ESGE–ESGENA position statement addressing sedation training in gastrointestinal endoscopy. This reinforces the idea that sedation is a formal competency, not something trainees should absorb casually by watching how different supervisors happen to work. Questions every endoscopy unit should now ask The most practical response to the 2026 ESGE–ESGENA endoscopy sedation guideline is a local audit. Unit leaders and clinical teams should examine whether their present system answers the following questions clearly: Is there a written sedation policy? Are patients assessed consistently before endoscopy? Are high-risk patients identified early? Does procedure complexity influence sedation planning? Are expected duration and therapeutic demands considered? Are monitoring responsibilities clearly assigned? Are observations documented consistently? Can staff recognize early sedation-related deterioration? Is airway rescue equipment immediately available? Are escalation pathways defined? Is anesthesia support requested according to clear clinical criteria? Are recovery and discharge standards consistent? Are staff competencies reviewed and updated? Are sedation-related adverse events audited? The point is not to create paperwork for its own sake. The point is to ensure that safety does not depend entirely on which clinician, nurse, or recovery staff member happens to be working that day. Reliable systems protect patients and professionals alike. What clinicians should not claim from the available source This article remains deliberately cautious because the accessible source confirms the guideline’s identity and publication details but does not present the complete recommendation text. The guideline should not be described as proving that one sedation model reduces mortality, improves adenoma detection, increases cannulation success, improves completion rates, or produces better patient satisfaction unless those conclusions are explicitly supported in the full document. Similarly, the accessible source does not justify claiming that the guideline mandates: One universal sedative drug One sedation-provider model Anesthesia involvement for every advanced procedure A single monitoring threshold A universal staffing ratio One discharge scoring system A procedure-specific algorithm applicable to every setting Those details must be checked in the full ESGE–ESGENA guideline. Clinical interpretation must also account for local regulations, available personnel, institutional policy, procedure volume, patient characteristics, and access to anesthesia services. A European guideline can inform practice internationally, but implementation should not ignore the realities of the local healthcare environment. Strengths of the 2026 ESGE–ESGENA guideline The guideline has several important strengths. First, it comes from ESGE and ESGENA, bringing together medical endoscopy and nursing perspectives. Second, it addresses a high-frequency clinical issue relevant to virtually every gastrointestinal endoscopy service. Third, it is positioned within endoscopic service guidance rather than being restricted to one disease or procedure category. Fourth, its 2026 publication provides a contemporary opportunity to reassess sedation practice as endoscopy becomes increasingly complex and patient populations become older and more medically vulnerable. Finally, the guideline encourages a systems-based view of sedation. This is important because adverse events rarely result from one decision alone. They often arise from an interaction between patient vulnerability, procedure demands, medication effects, monitoring, communication, staffing, and delayed escalation. Limitations of this interpretation This blog uses only information supported by the accessible source. The source confirms: The full guideline title ESGE and ESGENA involvement Publication in Endoscopy Online publication on July 21, 2026 DOI 10.1055/a-2898-6540 Its position within ESGE endoscopic service guidance The accessible page does not provide the full graded recommendations. Therefore, this article does not attempt to reproduce detailed guidance on medication selection, exact dosing, monitoring thresholds, staffing requirements, discharge scores, or procedure-specific sedation pathways. Clinicians and endoscopy-unit leaders should consult the complete guideline before changing formal protocols. This article is intended to explain why the guidance matters and how an experienced clinician might approach it—not to replace the original document. Clinical Takeaway The 2026 ESGE–ESGENA guideline on sedation for gastrointestinal endoscopy should encourage every endoscopy service to examine sedation as a complete patient-safety pathway. The central lesson is not that one sedation technique is correct for every patient. It is that sedation should be planned according to: Individual patient risk Procedure complexity Expected duration Required sedation depth Team competence Monitoring capability Recovery resources Availability of escalation and rescue support For gastroenterologists, sedation should be understood not merely as a way to make endoscopy tolerable, but as a form of procedural risk management. For trainees, it should be treated as a formal clinical competency. For endoscopy nurses and recovery teams, the guideline reinforces their central role in monitoring, communication, deterioration recognition, and safe discharge. For unit leaders, the practical next step is an audit: Are sedation decisions systematic, individualized, documented, monitored, and supported by trained staff? If the answer is uncertain, the guideline has already served a useful purpose. After all, the safest endoscopy units are not those that assume complications will never occur. They are the ones that have thought carefully about what to do when the routine procedure stops being routine. Five Key Clinical Takeaways The 2026 ESGE–ESGENA sedation guideline was published online in Endoscopy on July 21, 2026 , with DOI 10.1055/a-2898-6540 . It is a professional society guideline, not a clinical trial, and should not be presented as generating new randomized patient-level outcome data. Sedation should be viewed as a complete pathway involving pre-assessment, individualized planning, monitoring, rescue readiness, recovery, discharge, documentation, and training. The ESGE–ESGENA collaboration highlights the central role of multidisciplinary teamwork, particularly endoscopy nursing, monitoring, recovery, and escalation processes. Clinicians should use the complete guideline to review local sedation policies while avoiding claims about specific drugs, provider models, monitoring thresholds, or clinical outcomes that are not confirmed by the full document. Source Reference Triantafyllou K, Tziatzios G, Tham TC, Beilenhoff U, Lorenzo-Zúñiga V, Pouw RE, Roelandt P, van Malenstein H, Vilmann P, Voiosu T, Abu-Freha N, Becq A, Coron E, Garborg K, Hollenbach M, Kovacevic B, Manno M, Parrella A, Pontone S, Romańczyk M, Sá PA, Soria San Teodoro MT, Turnbull D, Sidhu R. Sedation for gastrointestinal endoscopy: ESGE and ESGENA Guideline. Endoscopy. Published online July 21, 2026. DOI: 10.1055/a-2898-6540 . Source: ESGE guideline page.

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